Phenlypyridine carbonyl piperazine derivative

ABSTRACT

The present invention relates to a compound which is represented by the following general formula and has type 4 phosphodiesterase inhibitory action, and uses and an intermediate compound thereof.  
                 
 
     (wherein  
     R1, R2: hydrogen, a halogen, a lower alkyl, a lower alkoxy, or the like,  
     R3, R4: hydrogen, a (substituted) lower alkyl, a halogen, or the like,  
     R5: hydrogen, a lower alkyd, a lower alkoxycarbonyl, or the like, and  
     n: 0 or 1).

TECHNICAL FIELD

[0001] The present invention relates to aphenylpyridinecarbonylpiperazine derivative useful as a medicament,particularly as a type 4 phosphodiesterase (PDE4) inhibitor.

BACKGROUND ART

[0002] Asthma which has been hitherto considered as a reversibleobstruction of airway is currently understood as a disease characterizedby airway hypersensitivity and airway obstruction derived from chronicairway inflammation involving a number of inflammatory cells. The numberof the patients has been increasing steadily and is predicted to furtherincrease hereafter.

[0003] For the treatment of asthma, inhale steroid drugs asantiinflammatory agents, and β-stimulants such as procaterol andxanthine derivatives such as aminophylline and theophylline asbronchodilators are now mainly used.

[0004] The inhale steroid drugs have a wide antiinflammatory action andare highly useful as asthma-treating drugs, but the necessity ofinstructing an appropriate inhalation method and the existence ofsteroid-resistant asthma patients have been pointed out (ASTHMA 13-1,69-73 (2000), Internal Medicine, 81, 485-490 (1998)).

[0005] The bronchodilators alleviate contraction of airway smooth muscleby increasing intracellular cyclic adenosine 3′,5′-monophosphate (cAMP)concentration through the activation of an intracellular CAMP producingenzyme, adenylate cyclase, or the inhibition of a CAMP hydrolyzingenzyme, phosphodiesterase (PDE) in airway smooth muscle (InternalMedicine, 69, 207-214 (1992)). It is known that increased intracellularCAMP concentration induces inhibition of the contraction of airwaysmooth muscle (Clin. Exp. Allergy, 22, 337-344 (1992), Drugs of theFuture, 17, 799-807 (1992)), which is effective in improving conditionsof asthma.

[0006] However, it is known that the xanthine derivatives expresssystemic side effects such as hypotension and cardiotonic action (J.Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551-564 (1985),J. Pharmacol. Exp. Ther., 257, 741-747 (1991)), and the β-stimulants areapt to cause desensitization and, when the dosage is increased, generateside effects such as finger tremor and palpitation.

[0007] On the other hand, chronic obstructive pulmonary disease (COPD)is a respiratory disease which relates to an abnormal inflammatoryreaction and is characterized by irreversible limitation of airflow, andis the fourth cause of death in the world at present (Executive summary.Global Initiative for Chronic Obstructive Lung Disease (GOLD), (2000)).Currently, as in the case of asthma, β-stimulators, anticholinergicdrugs, and xanthine derivatives such as aminophylline and theophyllineas bronchodilators are now generally used as drug therapy for COPD. Inaddition, inhale steroid drugs are also used since attention has beenattracted to the fact that the presence of chronic inflammation inairway participates in the obstructive disorder also in COPD, but it hasbeen reported that continuous treatment with inhale steroid does notimprove the long-term decrease of FEVI in COPD patients (N. Engl. J.Med. 340, 1948-53 (1999), Lancet 353, 1819-23 (1999), BMJ 320, 1297-303(2000), N. Engl. J. Med. 343, 1902-9 (2000)). Thus, an antiinflammatorydrug capable of improving conditions of COPD is highly desired.

[0008] It has been revealed that PDE is divided into at least sevenfamilies of from PDE1 to PDE7, and each of them has differentdistribution or function (Prog. Nucleic Acid Res. Mol. Biol. 63, 1-38(1999)). Particularly, PDE4 does not act upon cyclic guanosine3′,5′-monophosphate (cGMP) but specifically hydrolyze cAMP amongnucleotides, and its presence is recognized in both of airway smoothmuscle and infiltrating cells.

[0009] Also, it has been reported that PDE4 inhibitors show inhibitoryaction upon eosinophiles infiltration by antigens andplatelet-activating factors in guinea pig (Eur. J. Pharmacol., 255,253-256 (1994)) and inhibit liberation of detrimental proteins (MBP,ECP) from eosinophiles (Br. J. Pharmacol., 115, 39-47 (1995)). It hasbeen also reported that they show inhibitory action upon the contractionof airway smooth muscle by contractile substances (histamine,methacholine, LTD₄) (Br. J. Pharmacol., 113, 1423-1431 (1994)), inhibitproduction of IL-4, a cytokine which is said to deeply participate inasthma (J. Invest. Dermatol., 100, 681-684 (1993)), express inhibitoryaction upon the acceleration of vascular permeability in the airway(Fundam. Clin. Pharmacol., 6, 247-249 (1992)) and show inhibitory actionupon airway hypersensitivity (Eur. J. Pharmacol., 275, 75-82 (1995)).Thus, a PDE4 inhibitor is expected to be an asthma-treating agent.

[0010] Moreover, it has been reported that PDE4 inhibitors haveinfiltration inhibitory action upon neutrophiles which are considered tobe involved in airway inflammation in COPD (Pulm. Pharmacol. Ther. 2001Mar; 14(2): 157-164). Furthermore, PDE4 inhibitors are capable ofimproving respiratory function of COPD patients (Clin. Exp. Allergy.1999 Jun; 29 Suppl 2: 99-109). Thus the inhibitor is also expected to bea COPD-treating drug.

[0011] As a compound having PDE4 inhibitory activity, the followingcompound:

[0012] (wherein A, Y and B mean each a bond or the like, Z means apyridine ring or the like which may be substituted with R³, R³ meansCONR⁴R⁵ or the like, and R⁴ and R⁵ represent each (1) a saturated orunsaturated five- or six-membered heterocycle which may be substitutedwith one or two groups selected from C₁₋₄ alkyl, CO₂R⁷, CONH₂,CON(CH₃)₂, oxo, OH, NH₂ and N(CH₃)₂, (2) a saturated or unsaturatedsix-membered heterocycle having one hetero atom as an additional ringatom selected from O, S, NH, NCH₃, NCOCH₃ or NCH₂Ph, or (3) a quinolinering which may be substituted by fluorine, or the like) is disclosed inWO 94/12461. However, a part of phenylpyridinecarbonylpiperazinederivatives are included in the wide claims of the publication but nospecific compound thereof is described therein. Even asphenylpyridinecarboxamide derivatives, the publication only describesthe following 5-phenylpyridine-3-carboxamide.

DISCLOSURE OF THE INVENTION

[0013] The inventors have conducted extensive studies on compoundshaving an orally available satisfactory inhibitory activity upon PDE4.As a result, they have found that a novel pyridine-2-carbonylpiperazinederivative having a phenyl group at the 6-position has a potent PDE4inhibitory activity, and thus they have accomplished the invention.

[0014] Namely, the invention relates to a novelphenylpyridinecarbonylpiperazine derivative represented by the followinggeneral formula (I) or a pharmaceutically acceptable salt thereof and amedicament containing the same as the active ingredient.

[0015] (wherein each symbol has the following meaning:

[0016] R¹ and R²: the same or different from each other, H, a halogen, alower alkyl, O-a lower alkyl, O-(a lower alkyl substituted withhalogen(s)), NH₂, NH-a lower alkyl, N(a lower alkyl)₂, NHCO-a loweralkyl, O-a lower alkylene-NH-a lower alkyl, O-a lower alkylene-N(a loweralkyl)₂, O-a lower alkylene-CO₂R⁰, O-a lower alkylene-a hydrocarbon ringor O-a lower alkylene-a heterocycle, or R¹ and R² are combined to form—O-a lower alkylene-O—,

[0017] R⁰: H, a lower alkyl or CH₂—(an optionally substituted phenyl),

[0018] R³ and R⁴: the same or different from each other, H, anoptionally substituted lower alkyl, a halogen, CO₂R⁰, CONH₂, CON(R⁰)-(anoptionally substituted lower alkyl), an optionally substitutedhydrocarbon ring, an optionally substituted heterocycle, CO-(anoptionally substituted lower alkyl), CO-(an optionally substitutedhydrocarbon ring), CO-(an optionally substituted heterocycle) or CN, orR³ and R⁴ are combined to form a lower alkylene or oxo,

[0019] R⁵: H. a lower alkyl, CO₂R⁰, CONH₂, CON(R⁰)-a lower alkyl, anoptionally substituted hydrocarbon ring, an optionally substitutedheterocycle, a lower alkylene-an optionally substituted hydrocarbonring, a lower alkylene-an optionally substituted heterocycle, a loweralkenylene-an optionally substituted hydrocarbon ring, a loweralkenylene-an optionally substituted heterocycle, an lower alkylene-R⁵¹,a lower alkylene-CO₂R⁰, CO-a lower alkyl, CO-(an optionally substitutedhydrocarbon ring), CO-(an optionally substituted heterocycle), CO-alower alkylene-(an optionally substituted hydrocarbon ring), CO-a loweralkylene-(an optionally substituted heterocycle), CO—O-a loweralkylene-(an optionally substituted hydrocarbon ring), CO—O-a loweralkylene-(an optionally substituted heterocycle), CON(R⁰)(R⁵⁶),C(R⁵³)(R⁵⁴)-R⁵⁵ or a lower alkylene-C(R⁵³)(R⁵⁴)-R⁵⁵,

[0020] R⁵¹: CO-a lower alkyl, CO-(an optionally substituted hydrocarbonring), CO-(an optionally substituted heterocycle), CO-a loweralkylene-(an optionally substituted hydrocarbon ring), CO-a loweralkylene-(an optionally substituted heterocycle), CN, OH, O-a loweralkyl, O—(an optionally substituted hydrocarbon ring), O—(an optionallysubstituted heterocycle), O-a lower alkylene-(an optionally substitutedhydrocarbon ring), O-a lower alkylene-(an optionally substitutedheterocycle), S-a lower alkyl, S—(an optionally substituted hydrocarbonring), S—(an optionally substituted heterocycle), S-a lower alkylene-(anoptionally substituted hydrocarbon ring), S-a lower alkylene-(anoptionally substituted heterocycle), NH(R⁰), N(R⁰)₂, N(R⁰)-(anoptionally substituted hydrocarbon ring), N(R⁰)-(an optionallysubstituted heterocycle), N(R⁰)-a lower alkylene-(an optionallysubstituted hydrocarbon ring), N(R⁰)-a lower alkylene-(an optionallysubstituted heterocycle), N(R⁰)CO-a lower alkyl, N(R⁰)CO-(an optionallysubstituted hydrocarbon ring), N(R⁰)CO-(an optionally substitutedheterocycle), N(R⁰)CO-a lower alkylene-(an optionally substitutedhydrocarbon ring), N(R⁰)CO-a lower alkylene-(an optionally substitutedheterocycle), N(R⁰)CO—O-a lower alkyl, N(R⁰)CO—O-a lower alkylene-(anoptionally substituted hydrocarbon ring) or N(R⁰)CO—O-a loweralkylene-(an optionally substituted-heterocycle)

[0021] R⁵³, R⁵⁴ and R⁵⁵: the same or different from one another, H, alower alkyl, CO₂R⁰, CON(R⁰)(R⁵⁶), R⁵¹, or R⁵⁶,

[0022] R⁵⁶: an optionally substituted hydrocarbon ring, an optionallysubstituted heterocycle, a lower alkylene-an optionally substitutedhydrocarbon ring, a lower alkylene-an optionally substitutedheterocycle, a lower alkylene-R⁵¹ or a lower alkylene-CO₂R⁰,

[0023] n: 0 or 1,

[0024] provided that (1) when R⁵ is a group bonded with CO, or H, nrepresents 0, and (2) when both of R³ and R⁴ are each H, R⁵ represents agroup other than methyl, acetyl or benzyl; the same shall applyhereinafter).

[0025] Also, according to the invention, there is provided a medicament,particularly a PDE4 inhibitor, which comprises thephenylpyridinecarbonylpiperazine derivative or a salt thereof.

[0026] The following describes the invention in detail.

[0027] The term “alkyl”, “alkylene” and “alkenylene” as used herein eachmeans a straight or branched hydrocarbon chain. The “lower alkyl” is analkyl group having from 1 to 6 carbon atoms, preferably an alkyl grouphaving from 1 to 4 carbon atoms, more preferably methyl or ethyl. The“lower alkylene” means a divalent group formed by removing any onehydrogen atom from the above “lower alkyl” and is preferably an alkylenehaving from 1 to 4 carbon atoms, more preferably methylene, ethylene orpropylene. The “lower alkenylene” means a group having one or moredouble bonds at any position in the “lower alkylene” having two or morecarbon atoms, and is preferably an alkenylene having from 2 to 4 carbonatoms.

[0028] The “halogen” represents F, Cl, Br or I. The “lower alkylsubstituted with halogen(s)” means, for example, a lower alkylsubstituted with one or more halogens, and is preferably a C₁₋₆ alkylsubstituted with one or more fluorines, more preferably fluoromethyl,difluoromethyl, trifluoromethyl or trifluoroethyl.

[0029] The “hydrocarbon ring” means a monocyclic to tricyclichydrocarbon ring having from 3 to 14 carbon atoms, and includes acycloalkyl, a cycloalkenyl and an aromatic hydrocarbon, and a bridgedcycloalkyl and a spiro ring. Also, they may be condensed each other toform indanyl, tetrahydronaphthyl or the like.

[0030] The “cycloalkyl” is preferably a cycloalkyl having from 3 to 8carbon atoms, more preferably cyclopropyl, cyclopentyl or cyclohexyl.The “cycloalkenyl” is preferably a cycloalkenyl having from 5 to 8carbon atoms, more preferably cyclohexenyl. The “aromatic hydrocarbon”means an aromatic hydrocarbon group having from 6 to 14 carbon atoms,and is preferably phenyl or naphthyl, more preferably phenyl. The“bridged cycloalkyl” is preferably norbornyl or adamantyl.

[0031] The “heterocycle” is a saturated or unsaturated monocyclic totricyclic three- to eight-membered, preferably five- to seven-memberedheterocycle having, as ring atom(s), from 1 to 4 hetero atoms selectedfrom O, S and N, which may be condensed with each other or with acycloalkyl ring or benzene ring to form a bicyclic or tricyclicheterocycle. The ring atom, S or N may be oxidized to form an oxide ordioxide. The heterocycle includes a saturated heterocycle, an aromaticheterocycle, and a partially saturated heterocycle thereof, and in thesaturated heterocycle and partially saturated heterocycle, any carbonatom(s) may be substituted with an oxo group. Moreover, the heterocyclemay be bridged or may form a spiro ring, which includes an acetal ringderived from an oxo group, such as 1,3-dioxolan. The heterocycle ispreferably a five- to seven-membered saturated or unsaturated monocyclicheterocycle, and is more preferably pyrrolidine, pyridine, piperidine,morpholine, thiophene, thiazole, imidazole, tetrazole, pyrazine orpiperazine.

[0032] The term “optionally substituted” means “unsubstituted” or“having from 1 to 5 substituents which may be the same or different fromone another”.

[0033] The substituent in the “optionally substituted lower alkyl” ispreferably a hydrocarbon ring, a heterocycle, CO₂R⁰ or a group describedin R⁵¹.

[0034] The substituent in the “optionally substituted hydrocarbon ring”or the “optionally substituted hetercycle” is preferably a groupselected from the following G group.

[0035] G group: groups represented by (i) -X-a C₁-6 alkylene-A, (ii) -aC₁₋₆ alkylene-A, or (iii) -B.

[0036] X is 0, S, SO, SO₂, NH, N(a C₁₋₆ alkyl), SO₂NH, SO₂N(a C₁₋₆alkyl), NHSO₂, N(a C₁₋₆ alkyl)SO₂, CO, CO₂, O—CO, CONH, CON(a C₁₋₆alkyl), NHCO, N(a C₁₋₆ alkyl)CO or NHCONH,

[0037] A is —CN, —OH, —CO₂H, —CO₂-a C₁₋₆ alkyl, —NO₂, —SO₃H, —NH₂,—CONH₂, —SO₂NH₂, a C₁-₆ alkyl substituted with halogen(s), —NH-a C₁₋₆alkylene-O-a C₁₋₆ alkyl, —N(a C₁₋₆ alkyl)-a C₁₋₆ alkylene-O-a C₁₋₆alkyl, —N(-C₁₋₆ alkylene-O-a C₁₋₆ alkyl)₂, -a hydrocarbon ring, -aheterocycle, -X-a C₁₋₆ alkyl, -X-a C₁₋₆ alkyl substituted withhalogen(s), -X-a hydrocarbon ring, -X-a heterocycle, -X-a C₁₋₆alkylene-CN, -X-a C₁₋₆ alkylene-OH, -X-a C₁₋₆ alkylene-CO₂H, -X-a C₁₋₆alkylene-CO₂-a C₁₋₆ alkyl, -X-a C₁₋₆ alkylene-NO₂, -X-a C₁₋₆alkylene-SO₃H, -X-a C₁₋₆ alkylene-NH₂, -X-a C₁₋₆ alkylene-CONH₂, -X-aC₁₋₆ alkylene-SO₂NH₂, -X-a C₁₋₆ alkylene-a hydrocarbon ring or -X-a C₁₋₆alkylene-a heterocycle,

[0038] B is -a C₁₋₆ alkyl, -a halogen, a C₁₋₆ alkyl substituted withhalogen(s), or a group described in A.

[0039] The hydrocarbon ring and heterocycle in the above A and B hereinmay have from 1 to 5 substituents selected from a C₁₋₆ alkyl, a halogen,a C₁₋₆ alkyl substituted with halogen(s), CN, OH, O-a C₁₋₆ alkyl, NH₂,—NH-a C₁₋₆ alkyl, —N(a C₁₋₆ alkyl) ₂, S-a C₁₋₆ alkyl, SO-a C₁₋₆ alkyl,SO₂-a C₁₋₆ alkyl, SO₂NH₂, SO₂NH-a C₁₋₆ alkyl, SO₂N(a C₁₋₆ alkyl) ₂,NHSO₂-a C₁₋₆ alkyl, CO₂H, CO₂-a C₁₋₆ alkyl, CONH₂, CONH-a C₁₋₆ alkyl,CON(a C₁₋₆ alkyl)₂ and NHCO-a C₁₋₆ alkyl.

[0040] The substituent in the “optionally substituted phenyl” ispreferably a group shown in the above G group, more preferably a C₁₋₆alkyl, O-a C₁₋₆ alkyl or a halogen.

[0041] Preferable compounds in the invention are the followingcompounds:

[0042] The compounds wherein R¹ is O-a C₁₋₆ alkyl, more preferably O-aC₁₋₄ alkyl, particularly preferably O-methyl. The compounds wherein R2is a halogen, O-a C₁₋₆ alkyl or O-a C₁₋₆ alkylene-a hydrocarbon ring,more preferably a halogen, O-a C₁₋₄ alkyl or O-CH₂-a C₃₋₈ cycloalkyl,particularly preferably O-methyl. The compounds wherein R³ and R⁴ areeach H, a C₁₋₆ alkyl, or oxo, more preferably H or methyl, particularlypreferably H. Particularly preferably, the compounds wherein both of R¹and R² are each O-methyl, both of R³ and R⁴ are each H. and n is 0.Moreover, the compounds wherein R⁵ is an optionally substitutedhydrocarbon ring or an optionally substituted heterocycle, morepreferably an optionally substituted phenyl or an optionally substitutedpyridyl, the phenyl or pyridyl having one or two groups, preferably onegroup selected from the above G group.

[0043] Particularly preferable compounds in the invention are thefollowing compounds:1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-methoxyphenyl)piperazine,1-(4-{4-[6-(3-cyclopropylmethoxy-4-methoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)ethanone,1-(6-bromo-2-pyridyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine,4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}acetanilide,3-diethylamino-4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}propananilide,4-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)morpholine,1-[2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenoxy)ethyl]piperidin-4-ol,4-{2-[(6-{4-]6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl)piperazin-1-yl}-3-pyridyl}oxylethyl)morpholine,trans-5-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethylpiperazin-1-yl}phenyl)pentanoic acid and1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-{4-[(1-oxido-4-pyridyl)methoxy]phenyl}piperadine.

[0044] Depending on the kinds of substituents, the compounds of theinvention may exist in the form of geometrical isomers and tautomers,and isolated forms or mixtures of these isomers are included in theinvention.

[0045] Also, the compounds of the invention may have asymmetric carbonatoms in some cases, and (R) and (S) forms of optical isomers can existbased on these atoms. The invention includes all the mixtures andisolated ones of these optical isomers.

[0046] Furthermore, pharmacologically acceptable prodrugs are alsoincluded in the compounds of the invention. The pharmacologicallyacceptable prodrugs are compounds having groups which can be convertedinto certain groups of the invention such as NH₂, OH and CO₂H bysolvolysis or under a physiological condition. Examples of the groupswhich form prodrugs include those which are described in Prog. Med., 5,2157-2161 (1985) and “Iyakuhin no Kaihatsu (Pharmaceutical Research andDevelopment)” (Hirokawa Publishing Co., 1990) Vol. 7 Drug Design163-198.

[0047] The compounds of the invention may form acid addition salts or,depending on the kinds of the substituents, salts with bases. Such saltsare pharmaceutically acceptable salts, and their illustrative examplesinclude acid addition salts with inorganic acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid andphosphoric acid and organic acids such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamicacid, salts with inorganic bases such as sodium, potassium, magnesium,calcium and aluminum and organic bases such as methylamine, ethylamine,ethanolamine, lysine and ornithine, and ammonium salts.

[0048] In addition, the invention also includes various hydrates,solvates and polymorphic substances of the compound (I) of the inventionand salts thereof.

[0049] (Production Method)

[0050] The compound of the invention and pharmaceutically acceptablesalts thereof can be produced by applying various known syntheticmethods making use of the characteristics based on its fundamentalskeleton or the kind of substituent. In that case, depending on the kindof functional group, it is sometimes effective from the productiontechnical point of view to protect the functional group with anappropriate protective group or replace the group by a group, which canbe easily converted into the functional group, at the starting materialor intermediate stage. As such functional groups, there may bementioned, for example, the groups described in “Protective Groups inOrganic Synthesis (3rd Ed.)” edited by T. W. Greene and P. G. M. Wuts,which may be optionally used in response to the reaction conditions. Insuch a method, after the protective group is introduced and then areaction is carried out, the desired compound can be obtained byremoving the protecting group or converting the group into the desiredgroup as occasion demands. Moreover, as in the above protective group,the prodrug of the compounds of the invention can be produced byintroducing a specific group or carrying out a reaction using theobtained compound of the invention at the starting material orintermediate stage. The reaction can be carried out by applying a knownmethod such as usual esterification, amidation, or dehydration by thoseskilled in the art.

[0051] First Production Method

[0052] This production method is a method for producing the compound(Ia) of the invention from a carboxylic acid compound (II) by amidation.

[0053] The reaction can be carried out by condensing the compound (II)with a piperazine compound (III) in the presence of a condensing agentsuch as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) or1,1′-carbonyl-bis-1H-imidazole (CDI) and optionally a further additivesuch as N-hydroxysuccinimide (HONSu) or 1-hydroxybenzotriazole (HOBt).Alternatively, an active-ester compound of the compound (II) with theabove additive may be once isolated and then condensed with thepiperazine compound (III). Examples of the solvent include aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, tetrahydrofuran (THF), 1,4-dioxane and dimethoxyethane;halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane andchloroform; N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),pyridine, and the like. These solvents may be used solely or as amixture of two or more of them.

[0054] Second Production Method

[0055] The compounds of the invention wherein various substituents arepresent on the group R⁵ in the general formula (I) or the compoundswherein R¹ or R² is a group other than an alkoxy group can be easilysynthesized by reactions obvious for those skilled in the art ormodified methods thereof using the compounds of the invention asstarting materials. In particular, using the compound obtained by theabove first production method wherein R⁵ is H as a starting material,the conversion of R⁵ can be easily carried out by subjecting thecompound to various reactions. For example, the following reactions canbe applied.

[0056] (1) Alkylation by Nucleophilic Substitution

[0057] O-, S- or N-alkylation can be achieved by reacting a compoundhaving OH, SH or primary to tertiary amino group with an alkylatingagent such as an alkyl halide, e.g., an alkyl chloride, or an organicsulfonate ester. Alternatively, it can be also achieved by carrying outMitsunobu reaction. The reaction is carried out in an organic solventinert to the reaction, e.g., aromatic hydrocarbons, ethers, alcohols(methanol, ethanol, etc.), DMF, NMP, dimethyl sulfoxide (DMSO) or thelike, under from cooling to heating using the compounds in equivalentamounts or one of them in excess amount. It is sometimes advantageousfor smoothly progressing the reaction to carry out the reaction in thepresence of a base such as sodium hydride, potassium hydride, lithiumdiisopropylamide, lithium hexamethyldisilazide, sodium methoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate.

[0058] (2) Reductive Alkylation

[0059] The alkylation can be achieved by reacting a compound having aprimary or secondary amine with a carbonyl compound such as a ketone oran aldehyde. A usual method for reductive alkylation can be employed inthe reaction, and methods described for example in “JIKKEN KAGAKU KOZA(4th Ed.)” edited by The Chemical Society of Japan, vol. 22 (1992)(Maruzen) and the like may be mentioned.

[0060] (3) Amidation, Sulfonamidation and Esterification

[0061] Using a carboxylic acid or a sulfonic acid compound, theproduction can be achieved by the method of using a condensing agent inthe above first production method or the method of a reactive derivativethereof. As the reactive derivative of the carboxylic acid or sulfonicacid compound, a acid halide, an acid anhydride, an active ester or thelike can be employed. The reaction can be carried out by methodsdescribed for example in “JIKKEN KAGAKU KOZA (4th Ed.)” edited by TheChemical Society of Japan, vol. 22 (1992) (Maruzen) and the like.

[0062] (4) Hydrolysis

[0063] The compound of the invention having a carboxyl group can beproduced by hydrolyzing a carboxylate ester compound. A usual method forhydrolysis can be employed in the reaction, and methods described forexample in the deprotection of carboxyl group of “Protective Groups inOrganic Synthesis (3rd Ed.)” mentioned above can be applied.

[0064] (5) Oxidation

[0065] An oxide compound such as pyridine N-oxide can be produced byoxidizing a compound having a pyridine or an amino group. As theoxidizing agent, use can be made of an inorganic oxidizing agent such ashydrogen peroxide, Oxone (trade name, Aldrich) or sodium perborate; oran organic oxidizing agent such as peracetic acid, m-chloroperbenzoicacid or dimethyldioxirane. The reaction is carried out in a solventinert to the reaction, selected from halogenated hydrocarbons, aromatichydrocarbons, ethers, DMF, acetic acid and water, or without solvent,under from cooling to heating. At the reaction, the oxidizing agent canbe used in an equivalent amount or an excess amount relative to thestarting compound. It is sometimes advantageous for smooth progress ofthe reaction to carry out the reaction in the presence of an inorganicacid (preferably sulfuric acid, nitric acid, hydrochloric acid orhydrobromic acid), an organic acid (preferably acetic acid ortrifluoroacetic acid), or an inorganic base (preferably sodiumhydroxide, potassium hydroxide or sodium hydrogen carbonate).Alternatively, a sulfinyl or sulfonyl compound can be produced bysimilar oxidation using a sulfanyl compound.

[0066] (6) Catalytic Reduction

[0067] The compound of the invention having an OH group can be producedby subjecting a compound having an O-benzyl group to debenzylation. Forexample, use can be made of a usual method for catalytic reductionwherein the reaction is carried out under a hydrogen atmosphere in thepresence of palladium/carbon catalyst, and methods described in thedeprotection of OH group of “Protective Groups in Organic Synthesis (3rdEd.)” mentioned above can be also applied. Moreover, an alkenyl groupcan be converted into an alkyl group by the similar catalytic reduction.

[0068] Synthesis of Starting Materials

[0069] (wherein L represents a leaving group, P¹ represents a protectivegroup of a carboxyl group, and M represents a metal, respectively; thesame shall apply hereinafter).

[0070] The carboxylic acid compound (II) can be produced by hydrolyzinga compound (VI). The protective group of a carboxyl group in “ProtectiveGroups in Organic Synthesis (3rd Ed.)” mentioned above can be applied tothe protective group P¹, which can be removed by deprotection describedin the literature or a usual method such as hydrolysis.

[0071] The starting compound (VI) can be produced by coupling a pyridinederivative (IV) and an arylmetal compound (V) in the presence of acatalyst. Methods described in Comprehensive Organic Synthesis, Volume3, 481, 1991 and the like can be applied to the reaction. There may bementioned a halogen, trifluoromethanesulfonyloxy, or the like as theleaving group L, and hydroxyboron, an alkylboron, an alkoxyboron, amagnesium halide, a zinc halide, an alkyltin, an alkylcopper, or thelike as the metal M. As the catalyst, a palladium complex such astetrakistriphenylphosphinepalladium, palladium acetate or a nickelcomplex such as dichlorobis(triphenylphosphine)nickel orbis(1,5-cyclooctadiene)nickel is preferable. The reaction is carried outin a solvent inert to the reaction, selected from halogenatedhydrocarbons, ethers, aromatic hydrocarbons, DMF and water, or withoutsolvent, under from cooling to heating. At the reaction, the compound(IV) and the arylmetal compound (V) can be used in an equivalent amountor one of them in excess amount, and it is sometimes advantageous forsmoothly progressing the reaction to carry out the reaction in thepresence of a base such as triethylamine, pyridine,4-(N,N-dimethylamino)pyridine, sodium hydroxide, sodium carbonate,sodium hydride, sodium methoxide or potassium tert-butoxide.

[0072] (wherein Q represents CH or N, P² represents H or a protectivegroup of the amino group, and Z is a group selected from the G group orthe like, respectively).

[0073] A starting compound (IX) can be synthesized by subjecting an arylderivative (VII) to a coupling reaction or ipso substitution reactionwith a piperazine which may be protected. The production method of thestarting compound (VI) can be applied to the coupling reaction. Theconditions for alkylation by the above (1) nucleophilic substitution canbe applied to the ipso substitution reaction. Protective groups for anamino group described in the above “Protective Groups in OrganicSynthesis (3rd Ed.)” can be applied to the protective group p² and aftera reaction, the starting compound (IX) can be freed by deprotectiondescribed in the literature.

[0074] The reaction product obtained by each of the above productionmethods is isolated and purified as its free compound, salt or varioussolvates such as hydrate. The salt can be produced by carrying out ausual salt formation treatment.

[0075] The isolation and purification are carried out by employingusually used chemical techniques such as extraction, concentration,evaporation, crystallization, filtration, recrystallization and varioustypes of chromatography.

[0076] Various isomers can be isolated in the usual way making use ofthe difference in physicochemical properties between correspondingisomers. For example, optical isomers can be separated by a generaloptical resolution method such as a fractional crystallization orchromatography. Also, an optical isomer can be produced starting from anappropriate optically active starting compound.

[0077] Furthermore, the invention also relates to a novel intermediate,a carboxylic acid derivative represented by the general formula (IIa),which is useful in the production of thephenylpyridinecarbonylpiperazine derivative (I).

[0078] (wherein

[0079] R^(1a) represents a halogen, a lower alkyl, O-a lower alkyl, O—(alower alkyl substituted with halogen(s)), NH₂, NH-a lower alkyl, N(alower alkyl)₂, NHCO-a lower alkyl, O-a lower alkylene-NH-a lower alkyl,O-a lower alkylene-N(a lower alkyl)₂, O-a lower alkylene-CO₂R⁰, O-alower alkylene-a hydrocarbon ring, or O-a lower alkylene-a heterocycle,

[0080] R^(2a) represents H or a group described in R^(1a),

[0081] or R^(1a) and R^(2a) are combined to form —O-a lower alkylene-O—,

[0082] provided that (1) when R^(2a) is H, R^(1a) represents a groupother than methyl, ethyl, OMe, NH₂, NHMe or Cl, and (2) when R^(2a) ismethyl, R^(1a) represents a group other than methyl, respectively; thesame shall apply hereinafter).

[0083] The carboxylic acid compound (IIa) is included in the carboxylicacid compound (II) described in the above intermediate. The preferablegroups for R^(1a) and R^(2a) in the compound (IIa) are the same as thepreferable groups for R¹ and R² in the compound (I).

Industrial Applicability

[0084] Also, the compound (I) of the invention has excellent inhibitoryactivity of PDE4 and is therefore useful as an agent for preventingand/or treating respiratory diseases (e.g., bronchial asthma (includingatopic asthma), COPD, chronic bronchitis, pneumonic diseases and adultrespiratory distress syndrome (ARDS)) in which PDE4 participates.Particularly, it can be expected to be an agent for preventing and/ortreating bronchial asthma and COPD.

[0085] In addition, the compound of the invention is also useful as anagent for preventing and/or treating other diseases in which involvementof PDE4 is known, such as those in which a cytokine (IL-1, IL-4, IL-6and TNF (tumor necrosis factor)) or the like is concerned (e.g.,rheumatoid arthritis, ulcerative colitis, Crohn disease, sepsis, septicshock, endotoxin shock, Gram negative bacterial sepsis, toxic shocksyndrome, nephritis, hepatitis, infection (bacterial and viral) andcirculatory failure (heart failure, arteriosclerosis, myocardialinfarction, stroke) or the like).

[0086] Availability of the compound (I) of the invention was confirmedby the following tests.

TEST EXAMPLE 1 PDE4 Inhibitory Activity

[0087] 1) A solution containing PDE4 was purified from rat ventriclemuscle in the following manner. The heart excised from a male Wistar ratunder ether anesthesia was washed with physiological saline and then theventricle was separated. The thus separated ventricle was finely cutwith scissors and suspended in a buffer A (20 mM Bis-Tris, 50 mM sodiumacetate, 2 mM EDTA, 5 mM 2-mercaptoethanol, 2 mM benzamidene, 0.05 mMphenyl-methyl-sulfonyl fluoride, pH 6.5) containing 1% ProteaseInhibitor Cocktail For Mammalian Cell Extracts (SIGMA). Thereafter, thecells were disrupted using Polytron and subjected to ultracentrifugation(100,000 G, 60 minutes, 4° C.) to obtain a soluble fraction.

[0088] 2) The resulting soluble fraction was charged to a 2.6×10 cmQ-Sepharose column equilibrated with the buffer A. Next, the column waswashed with 1,200 ml of the buffer A to remove uncombined protein. Theprotein combined to the column was eluted using 750 ml of the buffer Acontaining a linear gradient sodium acetate solution of from 0.05 to1.00 M, and 110 tubes each containing 7 ml fraction were recovered. ThecAMP metabolizing PDE activity of each fraction obtained in the presenceor absence of cGMP and calcium/calmodulin was investigated. Eachfraction which showed cAMP metabolizing activity and received noinfluence on the cAMP metabolizing activity by the presence of cGMP orcalcium/calmodulin was used as a stock solution for the inspection ofPDE4 inhibitory activity.

[0089] 3) Each test compound in a desired concentration was allowed toundergo 10 minutes of the reaction at 30° C. in a reaction mixturecontaining 40 mM Tris-HCl (pH 8.0), 5 mM magnesium chloride, 4 mM2-mercaptoethanol, 1 pM cAMP, 1 μCi/ml [³H]cAMP and the PDE4 stocksolution. The reaction was stopped by adding ½ volume of 20 mg/mlpolylysine coated yttrium silicate SPA beads (Amersham) suspensioncontaining 18 mM zinc sulfate and 5 μM 3-isobutyl-1-methylxanthine(IBMX) to the reaction solution, and the radioactivity was measured.

[0090] A concentration of test compound which inhibits 50% of themetabolic activity of PDE4 was defined as IC₅₀ and calculated for eachcompound. By applying the above test method and the method described inWO 97/19078, inhibitory activity against PDE1, PDE2, PDE3 and PDE5 wasmeasured similarly.

[0091] As a result of the above measurement, it was revealed that thecompounds of Examples 2, 10, 15, 32, 43, 45, 77, 95, 99 and 112 have anIC₅₀ value of 12 nM or less for PDE4. Moreover, in the sameconcentration, they hardly exhibited inhibitory activity against PDE1,PDE2, PDE3 and PDE5. Accordingly, it was confirmed that the compound ofthe invention is a strong and selective PDE4 inhibitor.

TEST EXAMPLE 2 Oral Absorbability and Pharmacokinetic Profile EvaluationTest Using TNF-A Production Inhibitory Activity as the Index

[0092] 1) Each test compound suspended in purified water containing 0.5%methyl cellulose was orally administered to a eight-week-old male Fisherrat at a dose of 10 mg/kg. In the control group, a solvent (0.5% methylcellulose in purified water, 3 ml/kg) was administered in the samemanner. After the oral administration, blood samples were periodicallycollected in the presence of heparin from the caudal vein of each ratunder ether anesthesia, and plasma was prepared in the usual way.

[0093] 2) The plasma prepared above (final concentration 2.5%), RPMI1640medium containing 10% bovine fetal serum, 20 μl of whole blood of maleWister rat and LPS (final concentration 3 μg/ml) were dispensed to a96-well culture plate so that the total volume per 1 well was 200 μl,followed by culturing at 37° C. using a CO₂ incubator overnight. Afterthe completion of the culturing, the plate was centrifuged (1,500r.p.m., 10 minutes), the supernatant was recovered, and the amount ofTNF-A in the supernatant was measured using a commercially availableELISA kit.

[0094] As a result of this test, it was revealed that the compound ofthe invention has good oral absorbability.

[0095] Based on the results of the above inhibitory activity measuringtests, it was confirmed that the compound (I) of the invention exhibitsselective and potent inhibitory activity against PDE4 as well as goodoral absorbability, and thus it is evident that it is useful as an agentfor preventing and treating diseases in which PDE4 participates.

TEST EXAMPLE 3 Action on Antigen-induced Eosinophile Infiltration in RatAirway

[0096] An OA solution for sensitization (final concentration: OA; 1mg/ml, Al(OH)₃; 20 mg/ml) was administered intraperitoneally to afour-week-old Brown Norway female rat (Charles River Japan, Inc.,Kanagawa) continuously for 3 days at a dose of 1 ml per rat to effectantigen-sensitization. The first day of administration was assigned tobe Day 0. On Day 21 or 22, 1% OA/physiological saline was atomized bymeans of an ultrasonic nebulizer (NE-U12, Omron) and the sensitized ratwas exposed to the antigen by letting the rat inhale the atomized OA for20 minutes to induce infiltration of eosinophiles into airway. Inaddition, a group wherein physiological saline was inhaled for exposurewas used as a normal control group. A test compound was suspended in a0.5% MC aqueous solution and the suspension was administered orally 1hour before the antigen inhalation and exposure. The animal was underfasting state from the day before the antigen inhalation and exposureand, after the antigen inhalation and exposure, it was released from thefasting state. After 24 hours from the antigen inhalation and exposure,the animal was subjected to laparotomy under Nembutal anesthesia and wasexsanguinated from aorta abdominalis to death. Thereafter, a cannula (6Fr-Atom venous catheter, Atom) was inserted to the airway, andbronchoalveolar lavage (PAT) was carried out by repeating the operationof injecting and recovering 2 ml of physiological saline containingheparin (1 unit/ml) five times (10 ml in total). After the recovered BALliquid was centrifuged at 500×g (4° C., 10 minutes), the supernatant wasremoved and the precipitate (cell fraction) was re-suspended with 500 μlof physiological saline containing heparin (1 unit/ml). Total leukocyteconcentration in the re-suspended liquid was measured by means of ahemocyte-counting apparatus (celltac-α, Nihon Kohden Corporation) andthen a spread specimen was prepared and stained with a blood-stainingliquid for differentiation (Dif Quick, International ReagentsCorporation), then observed under the microscope to calculate theabundance ratio of eosinophiles from the morphological characteristic.Based on the total number of leukocytes and the eosinophile abundanceratio, total number of eosinophiles was calculated and thereby theeffect of the drug was evaluated.

TEST EXAMPLE 4 Action on LPS-induced Neutrophile Infiltration in RatAirway

[0097] Infiltration of neutrophiles into the airway was induced byadministering, within the airway by means of 200 μl sonde, a 10 μg/mlLPS (lipopolysaccharide E. coli 0127:B8 Boivin, DIFCO) solutiondissolved in physiological saline to a six-week-old Wister male rat(Charles River Japan, Inc., Kanagawa) anesthetized by administering anappropriate amount of a ketamine/xylazine mixed solutionintraperitoneally. In addition, a group wherein physiological saline wasadministered within the airway was used as a normal control group. Atest compound was suspended in a 0.5% MC aqueous solution and thesuspension was administered orally 1 hour before the LPS administrationwithin the airway. The animal was under fasting state from the daybefore the LPS administration within the airway and, after the LPSadministration within the airway, it was released from the fastingstate. After 24 hours from the LPS administration within the airway, theanimal was subjected to laparotomy under Nembutal anesthesia and wasexsanguinated from aorta abdominalis to death. Thereafter, totalleukocyte concentration was measured in a similar manner to the aboveTest Example 3. Furthermore, the abundance ratio of neutrophiles wassimilarly calculated from the morphological characteristic observedunder the microscope. Based on the total number of leukocytes and theneutrophile abundance ratio, total number of neutrophiles was calculatedand thereby the effect of the drug was evaluated.

[0098] The pharmaceutical preparation containing one or two or more ofthe compounds of the invention or salts thereof as the active ingredientis prepared using carriers, excipients and other additives which aregenerally used in the preparation of medicaments.

[0099] The administration may be either oral administration in the formof, e.g., tablets, pills, capsules, granules, powders or liquids orparenteral administration in the form of, e.g., intravenous orintramuscular injections, suppositories, transdermal preparations,transnasal preparations or inhalations. The dose is optionally decidedin response to each case, e.g., by taking symptoms, age and sex of eachpatient to be treated into consideration, but is usually approximatelyfrom 0.001 mg/kg to 100 mg/kg per day per adult in the case of oraladministration, which is administered once a day or by dividing into 2to 4 doses per day. Also, when intravenous administration is conducteddue to the symptoms, it is administered once or several times a daygenerally within the range of from 0.0001 mg/kg to 10 mg/kg per day peradult. Also, in the case of inhalation, it is administered once orseveral times a day generally within the range of from 0.0001 mg/kg to 1mg/kg per day per adult.

[0100] The solid composition for the oral administration according tothe invention is used in the form of, e.g., tablets, powders orgranules. In such a solid composition, one or more active substances aremixed with at least one inert excipient such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone or aluminum magnesium metasilicate. In the usualway, the composition may contain inert additives including a lubricantsuch as magnesium stearate and a disintegrating agent such ascarboxymethylstarch sodium or a solubilization assisting agent. Ifnecessary, tablets or pills may be coated with a film of sugar or agastric or enteric coating agent.

[0101] The liquid composition for oral administration contains, e.g.,pharmaceutically acceptable emulsions, liquids, suspensions, syrups andelixirs and contains a generally used inert solvent such as purifiedwater or ethanol. In addition to the inert solvent, this composition mayalso contain auxiliary agents such as a solubilizing agent, a moisteningagent and a suspending agent, as well as sweeteners, flavors, aromaticsand antiseptics.

[0102] The injections for parenteral administration include asepticaqueous or non-aqueous liquids, suspensions and emulsions. Examples ofthe aqueous solvent include distilled water for injection andphysiological saline. Examples of the non-aqueous solvent includepropylene glycol, polyethylene glycol, a plant oil such as olive oil, analcohol such as ethanol, and polysorbate 80 (trade name). Such acomposition may further contain a tonicity agent, an antiseptic, amoistening agent, an emulsifying agent, a dispersing agent, astabilizing agent and a solubilization assisting agent. Thesecompositions are sterilized, e.g., by filtration through abacteria-retaining filter, blending of a germicide or irradiation. Inaddition, these may be used by firstly making into sterile solidcompositions and dissolving them in sterile water or a sterile solventfor injection prior to their use.

[0103] The transmucomembranous preparations such as inhalations andtransnasal preparations are used in the form of solid, liquid orsemi-solid, and may be produced in accordance with hitherto knownmethods. For example, an excipient such as lactose or starch and furthera pH regulating agent, an antiseptic, a surfactant, a lubricant, astabilizing agent, and a thickening agent may be optionally addedthereto. For the administration, an appropriate device for inhalation orblowing can be used. For example, using a known device such as a metereddose-inhaling device or a nebulizer, the compound may be administeredsolely or as a powder of formulated mixture, or as a solution orsuspension in combination with a pharmaceutically acceptable carrier. Adry powder-inhaling device or the like may be a device for single use ora device for several uses, where a dry power or a capsule containing apower can be utilized. Alternatively, it may be in the form of apressurized aerosol spray wherein an appropriate propellant, e.g., asuitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbondioxide is employed.

BEST MODE FOR CARRYING OUT THE INVENTION

[0104] The invention will be specifically described below with referenceto Examples which, however, do not limit the scope of the invention.Methods for producing the starting compounds are shown in ReferenceExamples.

REFERENCE EXAMPLE 1

[0105] To a mixture of methyl 6-chloropyridine-2-carboxylate,3,4-dimethoxyphenylboric acid, dimethoxyethane and water were addedpalladium acetate, triphenylphosphine and sodium carbonate, and theywere reacted at 100° C. for 1 hour to obtain methyl6-(3,4-dimethoxyphenyl)pyridine-2-carboxylate. Thus obtained compoundwas reacted at 60° C. for 30 minutes in a mixed solution of THF-methanolwith adding a 1M aqueous sodium hydroxide solution, whereby6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid was obtained.

REFERENCE EXAMPLE 2

[0106] To a THF solution of 4-bromo-2-chloroanisole was added ann-butyllithium/n-hexane solution at -78° C., followed by 30 minutes ofstirring. Then, trimethyl borate was added and the whole was warmed toroom temperature, followed by 30 minutes of stirring. Using the residueobtained by evaporation of the solvent instead of3,4-dimethoxyphenylboric acid, an objective compound was obtained in asimilar manner to Reference Example 1.

REFERENCE EXAMPLE 3

[0107] Using 1-benzyloxy-4-bromo-2-methoxybenzene, an objective compoundwas obtained in a similar manner to Reference Example 2 with theexception that the hydrolysis was carried out in a 1M aqueous sodiumhydroxide solution at 100° C. for 2.5 days.

REFERENCE EXAMPLE 4

[0108] Using 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid andt-butoxycarbonylpiperazine,1-{[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(t-butoxycarbonyl)piperazine was obtained in a similar manner to Example 2 to be mentionedbelow. Further, a 4M hydrogen chloride/ethyl acetate solution was addedthereto and the whole was reacted to obtain an objective compound.

REFERENCE EXAMPLE 5

[0109] Using1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-piperazine-2-carboxylic acidand morpholine,1-benzyloxycarbonyl-4-(t-butoxycarbonyl)-2-[(morpholin-4-yl)carbonyl]piperazinewas obtained in a similar manner to Example 4 to be mentioned below. Inethyl acetate, a 4M hydrogen chloride/ethyl acetate solution was addedthereto and the whole was reacted to obtain1-benzyloxycarbonyl-2-[(morpholin-4-yl)carbonyl]piperazine. The compoundwas heated to reflux for 1 day in toluene in the presence ofbromobenzene, tris(dibenzylideneacetone)dipalladium(0),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium t-butoxide toobtain 1-benzyloxycarbonyl-2-morpholinocarbonyl-4-phenylpiperazine.Further, thus obtained compound was stirred at room temperature for 1.5days in ethanol in the presence of 10% palladium/carbon under a hydrogenatmosphere of normal pressure. After filtration of insoluble matter, theresidue obtained by evaporation of the solvent was dissolved in ethanol,10% palladium/carbon and ammonium formate were added thereto, and thewhole was stirred at an oil bath temperature of 70° C. for 2.5 days toobtain an objective compound.

REFERENCE EXAMPLE 6

[0110] To a DMF solution of 4-bromo-2-ethylphenol were added potassiumcarbonate and benzyl bromide, and the whole was stirred at an oil bathtemperature of 60° C. for 30 minutes to obtain benzyl(4-bromo-2-ethylphenyl) ether, which was then treated in a similarmanner to the first half of Reference Example 2 to obtain methyl6-(4-benzyloxy-3-ethylphenyl)pyridine-2-carboxylate. The obtainedcompound was stirred in a mixed solution of methanol and THF in thepresence of 10% palladium/carbon under a hydrogen atmosphere of normalpressure at room temperature for 24 hours and then thus obtained productwas dissolved in trifluoroacetic acid. Pentamethylbenzene was addedthereto under ice cooling and the whole was stirred at an oil bathtemperature of 50° C. for 1 hour and further at room temperature for 4.5days to obtain methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate.The obtained compound was treated with trifluoromethanesulfonicanhydride in pyridine to obtain methyl6-(3-ethyl-4-trifluoromethanesulfonyloxyphenyl)pyridine-2-carboxylate.Further, to a 1,4-dioxane solution of the ester compound obtained abovewere added tributylvinyltin, lithium chloride,tetrakis(triphenylphosphine)palladium(0), and2,6-di-t-butyl-4-methylphenol, and the whole was heated to reflux for 18hours. Thereafter, tetrakis(triphenylphosphine)palladium(0) was furtheradded thereto, followed by 2 days of heating under reflux. Then,potassium fluoride was added thereto at room temperature and the wholewas stirred at room temperature for 2 days to obtain methyl6-(3-ethyl-4-vinylphenyl)pyridine-2-carboxylate. The compound wastreated with a 1M aqueous sodium hydroxide solution in methanol toobtain an objective compound.

REFERENCE EXAMPLE 7

[0111] To a DMF solution of methyl6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate were added potassiumcarbonate and methyl iodide, and the whole was stirred at an oil bathtemperature of 70° C. for 2 hours to obtain methyl6-(3-ethyl-4-methoxyphenyl)pyridine-2-carboxylate, which was thenstirred in methanol and a 1M aqueous sodium hydroxide solution at an oilbath temperature of 60° C. for 1 hour to obtain an objective compound.

REFERENCE EXAMPLE 8

[0112] 4-Iodophenol was reacted with 2-chlorodimethylamioethanehydrochloride in DMF under heating in the presence of potassiumcarbonate to obtain [2-(4-iodophenoxy)ethyl]dimethylamine. The obtainedcompound was reacted in toluene under heating in the presence of t-butylpiperazine-1-carboxylate, sodium t-butoxide,tri(2-methylphenyl)phosphine and a catalytic amount oftris(dibenzylideneacetone)dipalladium(0) to obtain an objectivecompound.

REFERENCE EXAMPLE 9

[0113] 2,6-Dichloropyridine was reacted with t-butylpiperazine-1-carboxylate in N,N-dimethylimidazolidinone under heating inthe presence of potassium carbonate to obtain an objective compound.

REFERENCE EXAMPLE 10

[0114] In a mixed solvent of THF-methanol, methyl6-(3-benzyloxy-4-methoxyphenyl)pyridine-2-carboxylate was stirred in thepresence of palladium/carbon under a hydrogen atmosphere to obtainmethyl 6-(3-hydroxy-4-methoxyphenyl)pyridine-2-carboxylate. The obtainedcompound is reacted with cyclopropylmethyl bromide and potassiumcarbonate in DMF under heating to obtain methyl6-(3-cyclopropylmethoxy-4-methoxyphenyl) pyridine-2-carboxylate, whichwas further reacted in a mixed solvent of THF-methanol under heatingwith adding a 1M aqueous sodium hydroxide solution to obtain anobjective compound.

REFERENCE EXAMPLE 11

[0115] To a toluene solution of 4-bromo-2-chloroanisole were added1-(t-butoxycarbonyl)-piperazine,tris(dibenzylideneacetone)dipalladium(0),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium t-butoxide,followed by 4 hours of heating at an oil bath temperature of 110° C.Then, post-treatment and purification were carried out in a usual way toobtain an objective compound.

REFERENCE EXAMPLE 12

[0116] Trifluoroacetic acid was added to a chloroform solution of1-(t-butoxycarbonyl)-4-(3-chloro-4-methoxyphenyl)piperazine and thewhole was stirred for 30 minutes. Then, post-treatment and purificationwere carried out in a usual way to obtain an objective compound.

REFERENCE EXAMPLE 13

[0117] An NMP solution of 6-chloronicotinonitrile and(±)-trans-2,5-dimethylpiperazine was stirred at an oil bath temperatureof 120° C. for 1 hour to obtain an objective compound.

REFERENCE EXAMPLE 14

[0118] Potassium carbonate was added to an NMP solution of4-fluorobenzaldehyde and 1- (t-butoxycarbonyl)piperazine, and the wholewas stirred under heating. Then, post-treatment and purification werecarried out in a usual way to obtain an objective compound.

REFERENCE EXAMPLE 15

[0119] To piperazine melted at 150° C. was added 2-chlorobenzothiazole,followed by 1 hour of stirring. Then, post-treatment and purificationwere carried out in a usual way to obtain an objective compound.

REFERENCE EXAMPLE 16

[0120] To a mixture of 60% sodium hydride and THF were added dropwiseethyl diethylphosphonoacetate and further4-[4-(t-butoxycarbonyl)piperazin-1-yl]benzaldehyde under cooling to 0°C., followed by stirring. Then, post-treatment and purification werecarried out in a usual way to obtain ethyl3-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}acrylate. Further,catalytic reduction was carried out using palladium/carbon to obtain anobjective compound.

REFERENCE EXAMPLE 17

[0121] A DMSO solution of methyl 6-chloro-nicotinate and piperazine wasstirred at an oil bath temperature of 120° C. to obtain an objectivecompound.

REFERENCE EXAMPLE 18

[0122] Palladium/carbon was added to a methanol-THF mixed solution of1-(3-benzyloxy-4-nitrophenyl)-4-(t-butoxycarbonyl)piperazine, followedby stirring under a hydrogen atmosphere. Methyl orthoformate andp-toluenesulfonic acid were added to a methanol solution of2-amino-5-[1-(t-butoxycarbonyl)piperazin-4-yl]phenol obtained bypost-treatment and purification in a usual way, followed by heatingunder stirring. Then, post-treatment and purification were carried outin a usual way to obtain an objective compound.

REFERENCE EXAMPLE 19

[0123] N-Benzyliminodiacetic acid was reacted with CDI and 5-aminoindolein THF to obtain 4-benzyl-1-(1H-indol-5-yl)piperazine-2,6-dione, whichwas then reacted with lithium aluminum hydride in THF. Conc.hydrochloric acid and palladium hydroxide were added to an ethanolsolution of thus obtained compound and the whole was reacted under ahydrogen atmosphere of 3 atm for 65 hours to obtain an objectivecompound.

REFERENCE EXAMPLE 20

[0124] 4-(2-Chloropyrimidin-4-yl)piperazine-1-carbaldehyde and2-(dimethylamino)ethanol were reacted in DMF in the presence ofpotassium t-butoxide. Thus obtained compound was reacted in methanol inthe presence of potassium carbonate at 80° C. for 24 hours to obtain anobjective compound.

REFERENCE EXAMPLE 21

[0125] 4-[4-(t-Butoxycarbonyl)piperazin-1-yl]benzaldehyde and[3-(ethoxycarbonyl)propyl]triphenylphosphonium bromide were reacted inTHF in the presence of potassium t-butoxide to obtain ethyl5-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}-4-pentenoate, which wasthen subjected to catalytic reduction using palladium/carbon to obtainan objective compound.

REFERENCE EXAMPLE 22

[0126] 2-Bromo-6-iodopyridin-3-ol was reacted with potassium carbonateand benzyl bromide to obtain 3-(benzyloxy)-2-bromo-6-iodopyridine, whichwas then reacted in a similar manner to Reference Example 11, Example 22and Example 4, successively. Further, the resulting product wassubjected to catalytic reduction using palladium/carbon to obtain anobjective compound.

REFERENCE EXAMPLE 23

[0127] To a DMF solution of2-bromo-6-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyridin-3-olwere added 60% sodium hydride and ethyl 4-bromobutanoate, followed by 1hour of reaction at room temperature. Then, post-treatment andpurification were carried out in a usual way to obtain an objectivecompound.

REFERENCE EXAMPLE 24

[0128] 4-(2-Chloropyrimidin-4-yl)piperazine-1-carbaldehyde and benzylalcohol were treated in a similar manner to Reference Example 20 andExample 4, successively. Then, the resulting product was subjected tocatalytic reduction using palladium/carbon and further treated in asimilar manner to Reference Example 23 to obtain an objective compound.

REFERENCE EXAMPLE 25

[0129] To4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-1-(4-hydroxyphenyl)piperazinewere added 1,2-dibromoethane, a 2M aqueous sodium hydroxide solution,tetra-n-butylammonium hydrogen sulfate and water, followed by stirringat 60° C. After cooling of the reaction solution, water and chloroformwere added thereto, insoluble matter was removed by filtration, and thenthe resulting product was subjected to post-treatment and purificationin a usual way to obtain an objective compound.

REFERENCE EXAMPLE 26

[0130] Potassium t-butoxide was added to a DMF solution of2,5-dibromopyridine and 2-(dimethylamino)ethanol, and the whole wasstirred at an oil bath temperature of 100° C. for 3 hours to obtainN-{2-[(5-bromopyridin-2-yl)oxy]ethyl}—N,N-dimethylamine, which wasfurther treated in a similar manner to Reference Examples 11 and 12 toobtain an objective compound.

REFERENCE EXAMPLE 27

[0131] 2-(Benzyloxy)-6-bromonaphthalene was treated in a similar mannerto Reference Example 11, Example 22 and Example 4, successively, toobtain 1-[6-(benzyloxy)-2-naphthyl]-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine. The compound was dissolved intrifluoroacetic acid, pentamethylbenzene was added thereto under icecooling, and the whole was stirred at room temperature for 2 hours andfurther at an oil bath temperature of 40° C. for 2 hours to obtain anobjective compound.

REFERENCE EXAMPLE 28

[0132] To an acetonitrile solution of(±)-trans-4-(2,5-dimethylpiperazin-1-yl)benzaldehyde were addeddi(t-butoxycarbonyl) dicarbonate and 4-dimethylaminopyridine, followedby stirring. Then, post-treatment and purification were carried out in ausual way to obtain an objective compound.

REFERENCE EXAMPLE 29

[0133] An NMP solution of fluoro-4-nitrobenzene and(±)-trans-2,5-dimethylpiperazine was stirred at an oil bath temperatureof 120° C. for 3 hours to obtain(±)-trans-2,5-dimethyl-1-(4-nitrophenyl)piperazine, which was furthertreated in a similar manner to Example 4 to obtain an objectivecompound.

REFERENCE EXAMPLE 30

[0134] Methyl 3-oxobutyrate was added to an acetic anhydride solution of6-chloroquinoline 1-oxide, followed by 30 minutes of stirring at an oilbath temperature of 40° C. Thus obtained compound was added to 10%hydrochloric acid and the mixture was reacted at room temperature toobtain methyl (6-chloroquinolin-2-yl)acetate. The compound was furthertreated in a similar manner to Reference Example 11, Example 22 andExample 4, successively, to obtain an objective compound.

[0135] In a similar manner to the above Reference Examples or thefollowing Examples, the compounds of Reference Examples 31 to 69 shownin the following Tables 1 to 5 were obtained, respectively. Structuresand physicochemical data of the compounds of Reference Examples 1 to 69are shown in Tables 1 to 5.

EXAMPLE 1

[0136] To a THF (20 ml) solution of 740 mg of 2-oxo-3-phenylpiperazinewas added 638 mg of lithium aluminum hydride, followed by 3 hours ofheating under reflux. The reaction solution was cooled with ice andsodium sulfate decahydrate was added until gel disappeared in thereaction solution. After stirring for a while, insoluble matter wasremoved by filtration. Crude 2-phenylpiperazine obtained by evaporationof the solvent was added to a THF (20 ml) solution of 500 mg of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid, and 556 mg of WSChydrocloride and 260 mg of HOBt were further added thereto, followed by2 days of stirring at room temperature. Ethyl acetate was added to thereaction solution and the mixture was washed with water and brine. Afterdrying over anhydrous magnesium sulfate, the solvent was evaporated. Theobtained residue was purified by silica gel column chromatography(chloroform-methanol) to obtain colorless amorphous crystals (670 mg).The compound was dissolved in ethanol and 192 mg of fumaric acid wasadded thereto to form its fumarate salt, which was then recrystallizedfrom ethanol-ethyl acetate to obtain 607 mg of2-(3,4-dimethoxyphenyl)-6-(3-phenylpiperazine-1-carbonyl)pyridine 0.5fumarate as colorless crystals.

EXAMPLE 2

[0137] To a THF (20 ml) solution of 500 mg of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid were added 0.18 ml ofoxalyl chloride and one drop of DMF under ice cooling. After 30 minutesofstirring, the reaction solution was added dropwise to a pyridine (10ml) solution of 370 mg of 4-(4-methoxyphenyl)piperazine under icecooling. The mixture was warmed to room temperature and further stirredfor 30 minutes. Water was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed with brineand dried over anhydrous magnesium sulfate, and then the solvent wasevaporated. The residue was purified by silica gel column chromatography(chloroform-methanol) and recrystallization was further carried out fromethyl acetate-acetonitrile to obtain 370 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-methoxyphenyl)piperazineas colorless crystals.

EXAMPLE 3

[0138] In 15 ml of a 4M hydrogen cloride/ethylacetate solution, 0.62 gof t-butyl 4-[4-(2-dimethylaminoethoxy)phenyl]piperazine-1-carboxylatewas reacted. To a DMF (15 ml) solution of 0.86 g of a crude productobtained by evaporation of the solvent were added 0.34 g of WSChydrochloride, 0.24 g of HOBt and 0.41 g of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid, followed by 65 hoursof reaction at room temperature. Further, 0.34 g of WSC hydrochloride,0.24 g of HOBt and 0.50 ml of triethylamine were added thereto, followedby 8.5 hours of stirring at room temperature. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layer was washed with water and brine and dried over anhydrousmagnesium sulfate, and then the solvent was evaporated. The residue waspurified by silica gel column chromatography (ethyl acetate) and thenthus obtained compound was subjected to salt formation with 106 mg ofoxalic acid. Recrystallization (ethanol) was carried out to obtain 253mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(2-dimethylaminoethoxy)phenyl]piperazinedioxalate as pale yellow crystals.

EXAMPLE 4

[0139] To a THF (20 ml) solution of 500 mg of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid and 500 mg of1-(5-chlorothiazol-2-yl)piperazine were added 400 mg of WSChydrochloride, 320 mg of HOBt and 0.3 ml of triethylamine at roomtemperature. After 4 hours of stirring, water was added thereto,followed by extraction with ethyl acetate. The organic layer was washedwith water and brine and dried over anhydrous magnesium sulfate. Afterthe solvent was evaporated, the residue was purified by silica gelcolumn chromatography (chloroform-methanol) and recrystallization wasfurther carried out from diisopropyl ether-acetonitrile to obtain 560 mgof1-(5-chlorothiazol-2-yl)-4-[(6-3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazineas colorless crystals.

EXAMPLE 5

[0140] To a THF solution of ethyl4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)amino]butanoatewere added a 36% aqueous formalin solution, acetic acid and sodiumtriacetoxyborohydride, followed by stirring. Then, post-treatment andpurification were carried out in a usual way to obtain ethyl4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)-N-methylamino]butanoate.

EXAMPLE 6

[0141] To a THF (5 ml) and methanol (5 ml) mixed solution of 1.01 g ofethyl 3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)propanoate was added 5 ml of a 1M aqueous sodium hydroxidesolution, followed by 1 hour of stirring at room temperature. To thereaction solution was added 5 ml of a 1M aqueous hydrochloric acidsolution, followed by extraction with ethyl acetate. The organic layerwas washed with brine and dried over anhydrous magnesium sulfate. Afterthe solvent was evaporated, thus obtained crude crystals wererecrystallized from ethanol to obtain 673 mg of3-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)propanoic acid as colorless crystals.

EXAMPLE 7

[0142] In 15 ml of a 4M hydrochloric acid-ethyl acetate solution, 0.71 gof 2-chloro-6-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine was stirred atroom temperature for 7 hours. The solvent was evaporated to obtain acrude product of 2-chloro-6-(piperazin-1-yl)pyrazine hydrochloride. Theobtained crude product and 0.62 g of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid were treated in asimilar manner to Example 4 to obtain 594 mg of2-chloro-6-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazineas pale yellow crystals.

EXAMPLE 8

[0143] To a dichloromethane (10 ml) solution of 353 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(pyridin-4-yl)piperazinewas added 195 mg of m-chloroperbenzoic acid, followed by 1 hour ofstirring at 50C. An aqueous sodium thiosulfate solution was added to thereaction solution, followed by extraction with chloroform. The organiclayer was washed with water and brine and then dried over anhydrousmagnesium sulfate, and thereafter, the solvent was evaporated. Theresidue was purified by silica gel column chromatography(chloroform-methanol) and then recrystallization (ethanol-ethyl acetate)was carried out to obtain 294 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(1-oxidopyridin-4-yl)piperazine 1.5 hydrate as pale yellow crystals.

EXAMPLE 9

[0144] To an ethanol (70 ml) and water (25 ml) mixed solution of 2.5 gof1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-nitrophenyl)piperazinewere added 0.15 g of ammonium chloride and 3.1 g of reduced iron,followed by 2 hours of heating under reflux. The reaction solution wasfiltered through celite and the filtrate was concentrated under reducedpressure. An aqueous sodium hydrogen carbonate solution was added tothus obtained residue, followed by extraction with chloroform. Theorganic layer was washed with brine and then dried over anhydrousmagnesium sulfate, and thereafter, the solvent was evaporated. Theresidue was purified by silica gel column chromatography(chloroform-methanol) and further, crystallization was carried out fromacetonitrile-ethyl acetate to obtain 2.1 g of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-aminophenyl)piperazine as pale pink crystals.

EXAMPLE 10

[0145] To a DMF (10 ml) solution of 1.50 g of4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenolwere added 1.00 g of 4-chloromethylpyridine-N-oxide and 3.00 g of cesiumcarbonate, followed by 30 minutes of stirring at room temperature. Afterwarmed to 60° C., the mixture was further stirred for 30 minutes. Then,1.00 g of 4-chloromethylpyridine-N-oxide and 1.50 g of cesium carbonatewere added thereto and the whole was stirred at 60° C. for 1 hour. Aftercooling to room temperature, water was added thereto, followed byextraction with ethyl acetate. The organic layer was washed with waterand brine and then dried over anhydrous magnesium sulfate, andthereafter, the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform-methanol) and thenrecrystallization was carried out from ethanol to obtain 440 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(1-oxido-4-pyridylmethoxy)phenyl]piperazineas pale yellow crystals.

EXAMPLE 11

[0146] To an ethanol (6 ml) solution of 327 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazinemonohydrochloride were added 0.28 ml of triethylamine and 148 mg of2,4-dichloropyrimidine, followed by 2 hours of stirring at an oil bathtemperature of 90° C. After the solvent was evaporated, water was addedthereto, followed by extraction with chloroform. The organic layer waswashed with water and then dried over anhydrous magnesium sulfate, andthereafter, the solvent was evaporated. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate) and further,recrystallization was carried out from acetonitrile-diisopropyl ether toobtain 70 mg of2-chloro-4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidinemonohydrate as colorless crystals.

EXAMPLE 12

[0147] To a THF (5 ml) solution of 171 mg of4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoicacid was added 63 mg of CDI, followed by stirring at 60° C. Further, 52mg of CDI was added in twice thereto, and the whole was stirred at 60°C. for 24 hours in total. After the reaction solution was cooled to roomtemperature, 0.25 ml of aqueous ammonia was added thereto, followed by 6hours of stirring at room temperature. Further, 0.5 ml of aqueousammonia was added thereto and the whole was stirred at room temperature.Thus precipitated crude crystals were collected by filtration andrecrystallized from methanol-THF to obtain 68 mg of4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzamideas colorless crystals.

EXAMPLE 13

[0148] To an ethanol (8 ml) and THF (8ml) mixed solution of 159 mg ofbenzyl4-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl)phenylcarbamoyl}piperidine-1-carboxylate was added 18 mg of 10%palladium/carbon under an argon atmosphere. After 2 hours of stirring atroom temperature under a hydrogen atmosphere of normal pressure, themixture was filtered through celite and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform-methanol-aqueous ammonia) and thenrecrystallization was carried out from acetonitrile to obtain 70 mg of4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}piperidine-4-carboxyanilideas colorless crystals.

EXAMPLE 14

[0149] To a chloroform (5 ml) solution of 1.20 g of1-(benzofuran-5-yl)-4-(t-butoxycarbonyl)piperazine was added 5 ml oftrifluoroacetic acid at 0° C., and the whole was warmed to roomtemperature, followed by 1 hour of stirring. After neutralization with a1M aqueous sodium hydroxide solution, extraction with chloroform wascarried out. The organic layer was washed with brine. After drying overanhydrous magnesium sulfate, the solvent was evaporated. Using a 500 mgportion of 910 mg of 1-(benzofuran-5-yl)piperazine thus obtained, 420 mgof1-(benzofuran-5-yl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazinewas obtained as colorless crystals.

EXAMPLE 15

[0150] To a DMF (3 ml) solution of 355 mg of1-(4-aminophenyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazinewere added 130 mg of 1-chloro-2-(2-chloroethoxy)ethane, 77 mg of sodiumiodide and 249 mg of potassium carbonate, followed by overnight stirringat 100° C. After cooled to room temperature, the reaction solution wasconcentrated under reduced pressure and then water was added thereto,followed by extraction with chloroform. The organic layer was washedwith brine and then dried over anhydrous magnesium sulfate, andthereafter, the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform-methanol) and thencrystallization was carried out from ethanol-diethyl ether to obtain 210mg of4-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl)phenyl)morpholineas yellow crystals.

EXAMPLE 16

[0151] To a THF (2.5 ml) solution of 211 mg of1-(4-aminophenyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazinewere added 63.5 mg of methanesulfonyl chloride and 76.8 μl oftriethylamine, followed by overnight stirring at room temperature.Further, 79 mg of methanesulfonyl chloride and 103 μl of triethylaminewere added in twice thereto, and the whole was stirred at roomtemperature for 3 hours. Water was added to the reaction solution,followed by extraction with ethyl acetate. The organic layer was washedwith brine and then dried over anhydrous magnesium sulfate, andthereafter, the solvent was evaporated. The residue was purified bysilica gel column chromatography (chloroform-methanol) and thencrystallization was carried out from ethyl acetate-diisopropyl ether toobtain 175 mg of4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}methanesulfonanilideas pale purple crystals.

EXAMPLE 17

[0152] To 233 mg of ethyl[(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]acetatewas added 0.8 ml of conc. hydrochloric acid, followed by overnightstirring at room temperature. After the reaction solution wasconcentrated under reduced pressure, crystallization was carried outfrom 2-propanol-diisopropyl ether to collect[(4-f4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]aceticacid hydrochloride by filtration. The filtrate was concentrated underreduced pressure, and the residue was crystallized from hexane to obtain88 mg of[(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}benzoyl)amino]aceticacid hydrate as pale brown crystals.

EXAMPLE 18

[0153] To an NMP (7.5 ml) solution of 1.51 g of 2,5-dichloropyrazinewere added 2.00 g of 1-(t-butoxycarbonyl)piperazine and 2.00 g ofpotassium carbonate, followed by 1 hour of stirring under heating at100° C. The mixture was cooled to room temperature, and water was addedthereto, followed by extraction with ethyl acetate. The organic layerwas washed with water and brine and then dried over anhydrous magnesiumsulfate, and thereafter, the solvent was evaporated. The residue waspurified by silica gel column chromatography (chloroform-methanol) toobtain 2.73 g of 2-chloro-5-(4-t-butoxycarbonylpiperazin-1-yl)pyrazine.Using this compound,2-chloro-5-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrazinewas obtained in a similar manner to Example 14 as colorless crystals.

EXAMPLE 19

[0154] To a methanol (20 ml) solution of 460 mg of2-chloro-4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidine monohydrate was added 150mg of 10% palladium/carbon, followed by 23 hours of stirring at roomtemperature under a hydrogen atmosphere of normal pressure. Insolublematter was removed by filtration and the residue obtained by evaporationof the solvent was purified by silica gel column chromatography(chloroform-methanol) and further, recrystallization was carried outfrom acetonitrile-diisopropyl ether to obtain 83 mg of4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidineas colorless crystals.

EXAMPLE 20

[0155] To 297 mg of4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-1-(4-hydroxyphenyl)piperazinewere added 623 mg of [1,3]dioxolan-2-one and 147 mg of potassiumcarbonate, followed by 1.5 hours of stirring at 100° C. After themixture was cooled to room temperature, water and then 1M hydrochloricacid were added to the reaction solution, which was then neutralizedwith a saturated aqueous sodium hydrogen carbonate solution, followed byextraction with chloroform. The organic layer was washed with brine andthen dried over anhydrous magnesium sulfate, and thereafter, the solventwas evaporated. The residue was purified by silica gel columnchromatography (chloroform-methanol) and then recrystallization wascarried out from ethyl acetate to obtain 41 mg of2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenoxy)ethanolas pale yellow crystals.

EXAMPLE 21

[0156] To a DMF (5 ml) solution of 213 mg of6-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyridin-3-olwere added 81 mg of (2-chloroethyl)dimethylamine hydrochloride and 43 mgof 60% sodium hydride under ice cooling. After 1 hour of stirring at anoil bath temperature of 70° C., water was added thereto, followed byextraction with ethyl acetate. The organic layer was washed with brineand then dried over anhydrous magnesium sulfate, and thereafter, thesolvent was evaporated. The residue was purified by silica gel columnchromatography (chloroform to chloroform-methanol) and thus obtainedproduct (110 mg) was dissolved in ethanol and converted into its oxalatesalt by adding 40 mg of oxalic acid. Thereafter, the salt wasrecrystallized from ethanol to obtain 81 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[5-(2-dimethylaminoethoxy)-2-pyridyl]piperazineoxalate as colorless crystals.

EXAMPLE 22

[0157] To a chloroform (3 ml) solution of t-butyl4-[2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl)piperazin-1-yl}phenoxy)ethyllpiperazine-1-carboxylatewas added 0.427 ml of a 4M hydrogen chloride/ethyl acetate solution,followed by 2 days of stirring at room temperature. Further, 2 ml ofchloroform and 1 ml of a 4M hydrogen chloride/ethyl acetate solutionwere added thereto, and the whole was stirred at room temperatureovernight. Ethanol was added to the reaction mixture and crude crystalswere collected by filtration and recrystallized from methanol to obtain114 mg of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(2-piperazin-1-ylethoxy)phenyl]piperazinetetrahydrochloride hydrate as pale yellow crystals.

EXAMPLE 23

[0158] To an ethanol (37 ml) and water (13 ml) mixed solution of 1.42 gof(±)-trans-1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethyl-4-(4-nitrophenyl)piperazinewere added 0.16 g of ammonium chloride and 1.66 g of reduced iron,followed by 0.5 hour of heating under reflux. The reaction solution wasfiltered through celite and the filtrate was concentrated under reducedpressure. An aqueous saturated sodium hydrogen carbonate solution wasadded to thus obtained residue, followed by extraction with chloroform.The organic layer was washed with brine and then dried over anhydrousmagnesium sulfate, and thereafter, the solvent was evaporated. Theresidue was purified by silica gel column chromatography(chloroform-methanol) and the obtained compound was treated with a 4Mhydrogen chloride/ethyl acetate solution to form its salt. Then, thesolvent was evaporated and the residue was washed with ethyl acetate toobtain 582 mg of(±)-trans-4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethylpiperazin-1-yl}anilinehydrochloride hydrate as pale yellow crystals.

[0159] In a similar manner to the above Examples, the compounds ofExamples 24 to 115 shown in the following Tables 6 to 8 were obtained,respectively. Structures and physicochemical data of the compounds ofExamples 1 to 115 are shown in Tables 6 to 8.

EXAMPLES 116 to 147

[0160] To a DMF (0.7 ml) solution of 13 mg (0.05 mmol) of6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid were added a DMF (0.06ml) solution of each of various amine (0.06 mmol) and 25 mg ofdiisopropylethylamine. Then, a DMF (0.3 ml) solution of 23 mg of2-(1H-benzotriazol-1-yl)-1,1,3,13-tetramethyluronium hexafluorophosphatewas added thereto, followed by 24 hours of stirring at room temperature.PS-isocyanate (1.55 mmol/g, 100 mg; Argonaut) was added and the wholewas stirred at room temperature for 14 hours. The reaction solution wasfiltered, and 3 ml of chloroform and 3 ml of a 1M aqueous sodiumhydroxide solution were added to the filtrate, followed by stirring. Thechloroform layer was dried over anhydrous sodium sulfate and then thesolvent was evaporated to obtain each compound of Examples 116 to 147shown in the following Table 9. Structure and physicochemical data ofindividual compounds are shown in Table 9.

[0161] Furthermore, structures of the other compounds of the inventionare shown in Tables 10 to 13. These can be easily synthesized using theabove production methods, the methods described in Examples and methodsobvious for those skilled in the art, or modified methods thereof.

[0162] The following abbreviations are used in the following Tables.REx: Reference Example number, Ex: Example number, No: Compound number,Dat: physicochemical data (F: FAB-MS (M+H)⁺, FN: FAB-MS (M−H)⁻, EI:EI-MS (M⁺), MP: melting point (° C.), NMR1: δ (ppm) of characteristicpeaks of ¹H-NMR in CDCl₃, NMR2: δ (ppm) of characteristic peaks of¹H-NMR in DMSO-d₆, Sal: salt and contained solvent (Ox: oxalate, Fum:fumarate, blank column: free compound, the numeral before a component,for example, 2 HCl means dihydrochloride), Syn: production method (eachnumeral indicates a similarly produced Example number or ReferenceExample number), Me: methyl, Et: ethyl, cPr: cyclopropyl, tBu: t-butyl,Ph: phenyl, Bn: benzyl, Ac: acetyl, Pip: piperidin-1-yl, Pip4:piperidin-4-yl, Mor: morpholin-4-yl, Pipr: piperazin-1-yl and Pyrr:pyrrolidin-1-yl. In addition, the numeral before each substituent showsthe position of substitution, for example, 2-Cl means 2-chloro, 3,4-diMemeans 3,4-dimethyl, 2,3,4-triMe means 2,3,4- trimethyl, 4-Me-Pipr means4-methylpiperazin-1-yl and 3,4- (OCH₂O) means 3,4-methylenedioxy group,respectively. TABLE 1

REx Syn P² R³ R⁴ R⁵ Dat 5 — H

H Ph F: 276 13 — H Me Me

F: 217 28 — Boc Me Me 4-CHO-Ph F: 319 31 REx16 Boc Me Me

EI: 390 32 REx21 Boc Me Me

FN: 417 33 REx12 H Me Me

F:291 34 REx12 H Me Me

F: 319 35 REx13 H Me Me 4-CHO-Ph F: 219 36 REx13 H Me Me 4-Ac-Ph F: 233

[0163] TABLE 2

REx Syn R¹ R² Dat 1 — MeO MeO NMR2: 8.18(1H, d, J=8.0 Hz), 7.09(1H, d,J=8.0Hz), 3.87(3H, s); F: 260 2 — MeO Cl FN: 262 3 — BnO MeO F: 336 6 —CH₂═CH— Et F: 254 7 — MeO Et F: 258 10 — MeO cPr—CH₂O FN: 294 37 REx2MeO F FN: 246 38 REx2 MeO BnO NMR1: 6.95-7.05(1H, m), 5.28(2H, s),3.95(3H, s) 39 REx10 MeO CF₂H—O NMR1: 7.93-8.00(2H, m), 7.01(1H, d,J=8.0Hz), 1.35-1.42(1H, m)

[0164] TABLE 3

REx Syn R³ R⁴ R⁵ Dat 4 — H H H F: 328 22 — H H

F: 421 23 — H H

F: 535 24 — H H

F: 536 25 — H H

F: 526 27 — H H

F: 470 29 — Me Me 4-NO₂-Ph F: 477 30 — H H

F: 527 40 REx25 H H

F: 506 41 REx25 H H

F: 534 42 REx25 H H

F: 576 43 REx25 H H

F: 534 44 REx25 H H

F: 534 45 REx25 H H

F: 632 46 REx25 H H

F: 533 47 Ex5 H H

F: 664 48 Ex5 Me Me

F: 532 49 Ex5 Me Me

F: 560 50 REx12 & Ex5 H H

NMR1: 6.97(1H, d, J=8.4 Hz), 4.12(2H, q, J=7.2 Hz), 2.89(2H, t, J=7.6Hz)51 REx12 & Ex5 H H

NMR1: 6.97(1H, d, J=8.8 Hz), 4.12(2H, q, J=7.2 Hz), 2.84(2H, t, J=7.6Hz)

[0165] TABLE 4

REx Syn R⁵ Dat 8 —

F: 350 9 —

F: 299 11 — 3-Cl-4-OMe-Ph NMR1: 6.99(1H, d, J=2.8Hz), 3.85(3H, s),1.48(9H, s) 14 — 4-CHO-Ph NMR1: 9.80(1H, s), 3.37-3.40 (4H, m), 1.49(9H,s) 16 —

NMR1: 4.12(2H, q, J=7.2Hz), 2.87(2H, t, J=7.6Hz), 1.48(9H, s) 18 —

NMR1: 7.97(1H, s), 3.15-3.19 (4H, m), 1.49(9H, s) 21 —

NMR1: 4.12(2H, q, J=7.2Hz), 2.31(2H, t, J=7.2Hz), 1.48(9H, s) 52 REx113-F-4-OMe-Ph NMR1: 6.72(1H, dd, J=14, 2.8Hz), 3.85(3H, s), 1.48(9H, s)53 REx11

NMR1: 7.58(1H, d, J=2.4Hz), 3.07-3.09(4H, m), 1.49(9H, s) 54 REx114-(NEt₂)-Ph F: 334 55 REx14

NMR1: 7.91(1H, d, J=2.4Hz), 3.58-3.61(4H, m), 1.49(9H, s) 56 REx142-Cl-4-Ac-Ph NMR1: 7.07(1H, d, J=8.8Hz), 3.08-3.12(4H, m), 1.49(9H, s)57 REx14

NMR1: 9.80(1H, s), 3.54-3.58 (4H, m), 1.49(9H, s) 58 REx16

NMR1: 6.60(1H, d, J=8.8Hz), 4.12(2H, q, J=7.2Hz), 2.56 (2H, t, J=7.6Hz)59 REx10 & REx14

NMR1: 8.01(1H, d, J=8.4Hz), 5.22(2H, s), 1.49(9H, s)

[0166] TABLE 5 REx Syn R⁵ Dat 12 — 3-Cl-4-OMe-Ph F: 227 15 —

F: 220 17 —

F: 222 19 —

EI: 201 20 —

F: 252 26 —

F: 251 60 REx12 3-F-4-OMe-Ph F: 211 61 REx12

NMR2: 8.26(1H, d, J=2.4Hz), 7.97(1H, d, J=2.4Hz), 2.81-2.84 (4H, m) 62REx12 4-(NEt₂)-Ph F: 234 63 REx11 & REx12

NMR1: 7.96(1H, d, J=2.4Hz), 7.82(1H, d, J=2.4Hz), 3.84(3H, s) 64 REx11 &REx12

EI: 213 65 REx11 & REx12

F: 242 66 REx13 3-CF₃-4-Ac-Ph F: 273 67 REx13 3-OH-4-Ac-Ph F: 221 68REx13

F: 209 69 REx13 & REx12

F: 199

[0167] TABLE 6

Ex Syn

Dat Sal 1 —

NMR2: 7.63-7.73(2H, m), 4.52 (1H, m), 2.77-3.33(4H, m); MP: 180-181 0.5Fum 23

NMR2: 8.09-7.93(2H, m), 7.76-7.64(2H, m), 1.02(3H, d, J=6.3 Hz); MP205-210 HCl H₂O 24 Ex4

NMR2: 7.08(1H, dd, J =8.3, 3.0 Hz), 6.98-6.94(2H, m), 4.08-4.01 (1H, m);MP: 147-148 25 Ex1

NMR2: 7.93(1H, t, J=7.8Hz), 3.86 (3H, s), 2.09(1H, m) MP: 173-176(dec.)Fum 26 Ex3

NMR2: 1.10-1.13(3H, m), 1.31-1.37(3H, m), 2.44(3H, s); MP: 134-135 27Ex6

NMR2: 0.96-0.99(3H, m), 3.82-3.84(6H, m), 7.05-7.11(2H, m); MP: 160-16228 Ex6

NMR2: 0.95-0.98(3H, m), 1.93-1.96(2H, m), 3.81-3.84(6H, m); MP: 124-1273 H₂O 29 Ex4

NMR2: 8.50(1H, d, J=2.0Hz), 3.83(3H, s), 3.82(3H, s), 1.33-1.14 (6H, m);MP: 93-99 30 Ex15

NMR1: 7.87-7.66(3H, m), 3.06-3.03(4H, m), 1.12-1.04(3H, m); MP: 167-17231 Ex8

NMR2: 3.81(3H, s), 5.24(2H, s), 8.58-8.60(2H, m); MP: 171-174

[0168] TABLE 7

Ex Syn R⁵ Dat Sal 2 — 4-OMe-Ph NMR1: 7.84(1H, t, J=7.8Hz), 3.96 (3H, s),3.78(2H, s); MP: 169-172 3 —

NMR2: 3.85(3H, s), 3.82(3H, s), 3.13-3.16(4H, m), 2.79(6H, s); MP:136-137 2 Ox 4 —

NMR1: 7.01(1H, m), 6.98(1H, d, J=8.3Hz), 3.56-3.61(4H, m); MP: 141-143 5—

F: 547 6 —

NMR2: 12.06(1H, s), 7.53(1H, d, J=7.4Hz), 2.73(2H, t, J=7.6Hz); MP:169-171 7 —

NMR2: 8.32(1H, s), 7.90(1H, s), 3.88 (3H, s), 3.83(3H, s); MP: 160-161 8—

NMR2: 8.28-8.30(2H, m), 3.87(3H, s), 3.83(3H, s); F: 421 1.5 H₂O 9 —4-NH₂-Ph NMR2: 4.62(2H, br s), 3.85(3H, s), 2.98-3.03(4H, m); Mp:164-165 10 —

NMR2: 3.82(3H, s), 5.05(2H, s), 8.19-8.23(2H, m); MP: 182-183 11 —

NMR1: 8.10(1H, d, J=6.3Hz), 6.98 (1H, d, J=8.7Hz), 6.43(1H, d, J=6.3Hz); MP: 98-100 H₂O 12 — 4-CONH₂-Ph NMR2: 3.85(3H, s), 7.03(1H, br s),7.68-7.79(5H, m); MP: 237-240 13 —

NMR2: 1.44-1.54(2H, m), 3.85(3H, s), 9.59(1H, s); MP: 217-219 14 —

NMR1: 6.97(1H, d, J=8.3Hz), 6.69-6.71(1H, m), 3.20-3.30(4H, m); MP:176-178 15 —

NMR2: 3.69-3.73(6H, m), 3.85(3H, s), 6.85-6.91(4H, m); MP: 129-130 16 —4-(NHSO₂Me)-Ph NMR2: 2.88(3H, s), 3.82(3H, s), 9.28(1H, s); MP: 168-17017 —

NMR2: 3.82(3H, s), 8.55(1H, t, J=5.8Hz), 12.50(1H, br s); MP: 114-117H₂O 18 —

NMR1: 8.11(1H, d, J=1.5Hz), 6.98 (1H, d, J=8.3Hz), 3.69-3.80(4H, m); MP:160-162 19 —

NMR1: 8.63(1H, s), 8.26(1H, d, J=6.3Hz), 6.98(1H, d, J=8.3Hz); MP:138-139 20 —

NMR2: 3.65-3.72(4H, m), 3.82(3H, s), 4.80(1H, t, J=5.4Hz); MP: 111-11321 —

NMR1: 6.66(1H, d, J=8.8Hz), 3.97 (3H, s), 3.95(3H, s), 2.91(6H, s); MP:144-147 Ox 22 —

NMR2: 3.82(3H, s), 3.84(3H, s), 7.68-7.72(2H, m) MP: 155-158 4 HCl H₂O32 Ex2 4-Ac-Ph NMR1: 7.78(1H, dd, J=8.3, 1.0Hz), 3.96(3H, s), 2.53(3H,s); MP: 161-163 33 Ex2 4-NMe₂-Ph NMR2: 3.85(3H, s), 3.82(3H, s), 3.05-3.08(4H, m), 2.79(6H, s); MP: 159-161 34 Ex4

NMR2: 8.36(1H, d, J=0.9Hz), 7.09 (1H, d, J=8.0Hz), 3.86(3H, s), 3.82(3H, s); MP: 122-124 35 Ex4

NMR2: 8.19(2H, d, J=5.9Hz), 3.86 (3H, s), 3.82(3H, s), 3.45-3.52(4H, m);MP: 155-156 36 Ex4 2-Cl-4-OMe-Ph NMR2: 7.15(1H, d, J=9.0Hz), 7.05 (1H,d, J=3.0Hz), 6.91(1H, dd, J= 9.0, 3.0Hz); MP: 155-156 37 Ex4 4-CN-PhNMR2: 8.06(1H, d, J=7.8Hz), 3.85 (3H, s), 3.47-3.54(4H, m); MP: 146-14838 Ex4 4-CO₂Et-Ph NMR2: 3.86(3H, s), 3.45-3.51(4H, m), 1.29(3H, t,J=7.3Hz); MP: 112-114 39 Ex5 —CH₂-(2-OH-3-OMe-Ph) NMR1: 7.54(1H, dd,J=8.3, 2.0Hz), 3.78(2H, s), 2.76-2.66(4H, m); MP: 155-158 40 Ex5

NMR1: 6.97(1H, d, J=8.3Hz), 3.98 (3H, s), 2.09(3H, s); MP: 120-122 41Ex4 & Ex7

NMR2: 3.86(3H, s), 3.83(3H, s), 2.75(3H, d, J=4.4Hz); F: 530 2 HCl 2 H₂O42 Ex4 & Ex7

NMR2: 8.67(1H, t, d=5.4Hz), 3.86 (3H, s), 3.83(3H, s), 2.82(3H, s),2.80(3H, s); F: 518 2 HCl 2 H₂O 43 Ex3 4-NHAc-Ph NMR2: 1.99(3H, s),3.85(3H, s), 9.71(1H, s); MP: 201-203 44 Ex3 4-(NHCO-Ph)-Ph NMR2:3.82(3H, s), 6.98(2H, d, J=9.3Hz), 10.07(1H, s); MP: 169-171 45 Ex4

NMR2: 1.19(6H, t, J=7.4Hz), 2.72-2.75(2H, m), 10.02(1H, s); MP: 131-134Ox 46 Ex6 4-CO₂H-Ph NMR2: 3.86(3H, s), 6.99(2H, d, J=9.3Hz), 12.32(1H,br s); MP: 209-211 47 Ex4 4-OH-Ph NMR2: 3.84(3H, s), 6.82(2H, d,J=8.8Hz), 8.88(1H, s); MP: 177-179 48 Ex4 4-NO₂-Ph NMR2: 3.86(3H, s),7.04(2H, d, J=9.2Hz), 8.06-8.10(3H, m); MP: 142-144 49 Ex4

NMR1: 7.05(1H, d, J=9.8Hz), 6.98 (1H, d, J=8.3Hz), 6.89(1H, d, J=9.3Hz), 4.04(3H, s); MP: 171-172 50 Ex4

NMR1: 7.58(1H, dd, J=8.3, 2.0Hz), 6.98(1H, d, J=8.3Hz), 3.85(3H, s),3.40-3.28(4H, m); MP: 158-159 51 Ex4 3-Cl-4-OMe-Ph NMR1: 6.98(1H, d,J=8.8Hz), 3.86 (3H, s), 3.13-3.24(4H, m); MP: 158-159 52 Ex4

NMR1: 7.57(1H, dd, J=8.3, 2.4Hz), 6.94(1H, d, J=9.7Hz), 3.86-3.74 (4H,m); MP: 161 53 Ex4 4-Ac-3-CF₃-Ph NMR2: 2.52(3H, s), 3.82(3H, s),7.83(1H, d, J=8.7Hz); MP: 142-143 54 Ex4 3-F-4-OMe-Ph NMR1: 6.97(1H, d,J=8.3Hz), 3.85 (3H, s), 3.13-3.24(4H, m); MP: 155-156 55 Ex4

NMR1: 8.74(1H, dd, J=4.4, 1.5Hz), 3.97(3H, s), 3.95(3H, s), 3.50-3.38(4H, m); MP: 144-145 56 Ex4

NMR2: 3.85(3H, s), 4.03-4.21(4H, m), 6.46-6.49(2H, m); MP: 187-188 57Ex4 4-SO₂NH₂-Ph NMR2: 3.85(3H, s), 7.05-7.10(5H, m), 7.65(2H, d,J=9.3Hz); MP: 213-214 58 Ex3 4-Ac-3-OH-Ph NMR2: 2.49(3H, s), 3.86(3H,s), 12.76(1H, s); MP: 135-137 59 Ex4

NMR1: 8.43(1H, d, J=1.9Hz), 3.90 (3H, s), 3.87-3.82(4H, m); MP: 162-16360 Ex6

NMR2: 3.84(3H, s), 4.58(2H, s), 12.90(1H, br s); MP: 143-145 H₂O 61 Ex4

NMR1: 9.04(1H, d, J=2.9Hz), 6.98 (1H, d, J=8.3Hz), 6.61(1H, d, J=9.2Hz); MP: 183-184 62 Ex3

NMR2: 2.56-2.59(4H, m), 3.59(3H, s), 9.78(1H, s); MP: 140-142 63 Ex4

NMR1: 6.52(1H, d, J=8.3Hz), 3.99 (3H, s), 3.95(3H, s), 3.75-3.68(4H, m);MP: 107-109 64 Ex4

NMR1: 8.15(1H, d, J=2.4Hz), 6.97 (1H, d, J=8.3Hz), 3.55-3.64(4H, m); MP:140-142 65 Ex4

NMR1: 7.09-7.13(1H, m), 6.98(1H, d, J=8.3Hz), 3.79-3.83(4H, m); MP:172-173 66 Ex10

NMR2: 1.71-1.76(4H, m), 3.82(3H, s), 4.26(2H, t, J=4.9Hz); MP: 161-1651.5 Ox 67 Ex14 2-Cl-4-Ac-Ph NMR1: 7.04(1H, d, J=8.3Hz), 6.97 (1H, d,J=8.3Hz), 2.56(3H, s); MP: 164-165 68 Ex4

NMR1: 8.81(1H, d, J=2.5Hz), 3.98 (3H, s), 3.95(3H, s), 3.88(3H, s); MP:157-159 69 Ex4

NMR2: 1.20(3H, t, J=6.9Hz), 3.82 (3H, s), 8.63-8.66(1H, m); MP: 83-85 70Ex6

NMR2: 1.59-1.73(4H, m), 3.85(3H, s), 12.02(1H, s); MP: 79-81 H₂O 71 Ex14

NMR1: 7.98(1H, s), 6.98(1H, d, J=8.3Hz), 3.28-3.41(4H, m); MP: 151-15372 Ex12

NMR2: 7.78(1H, br), 7.16(1H, br), 6.88(1H, d, J=8.8Hz), 3.87(3H, s); MP:243-244 73 Ex3 4-CH₂OH-Ph NMR2: 3.82(3H, s), 4.39(2H, d, J=5.9Hz),4.96(1H, t, J=5.9Hz); MP: 150-152 74 Ex4

NMR1: 8.41(1H, s), 6.98(1H, d, J=8.3Hz), 3.98(3H, s); MP: 119-120 75Ex10 4-Ac-3-OMe-Ph NMR2: 2.44(3H, s), 3.88(3H, s), 0.5 6.53(1H, s); MP:117-118 H₂O 76 Ex4

NMR2: 4.09(2H, S), 10.23(1H, s), 16.22(1H, br); MP: 217-219 0.5 H₂O 77Ex4

NMR1: 6.55(1H, d, J=8.3Hz), 4.00 (3H, s), 3.95(3H, s), 3.75-3.66(4H, m);MP: 144-145 78 Ex4

NMR1: 7.32(1H, d, J=8.8Hz), 3.96 (3H, s), 3.94(3H, s), 3.31-3.18(4H, m);MP: 193-194 79 Ex6

NMR2: 3.85(3H, s), 9.75(1H, s), 12.09(1H, br); MP: 167-170 80 Ex6

NMR2: 1.28-1.43(4H, m), 3.85(3H, s), 11.97(1H, br s); MP: 102-109 H₂O 81Ex4

NMR2: 4.53(1H, t, J=4.9Hz), 3.88 (3H, s), 3.83(3H, s), 3.31-3.18(4H, m),2.81(6H, s); MP: 180-181 Ox 82 Ex4 2-OMe-Ph NMR2: 3.79(3H, s), 3.85(3H,s), 6.87-7.02(4H, m); MP: 162-163 83 Ex6

NMR2: 1.91(2H, quintet, J=6.8Hz), 3.85(3H, s), 12.12(1H, br s); MP:109-112 84 Ex6

NMR2: 6.13(1H, d, J=7.3Hz), 3.87 J=7.6Hz); MP: 182-185 85 Ex6

NMR1: 7.93(1H, d, J=2.9Hz), 3.97 (3H, s), 3.94(3H, s), 2.57(1H, t,J=7.1Hz); MP: 122-124 86 Ex10

NMR2: 1.22(6H, t, J=7.3Hz), 3.45-3.48(2H, m), 3.82(3H, s); MP: 97-99 2Ox H₂O 87 Ex6

NMR1: 6.97(1H, d, J=8.8Hz), 6.63 (1H, d, J=8.8Hz), 2.61(2H, t, J=7.3Hz);MP: 190-191 88 Ex6

NMR2: 1.66-1.80(4H, m), 3.82(3H, s), 12.01(1H, s); MP: 176-178 89 Ex124-(CONHMe)-Ph NMR2: 2.75(3H, d, J=3.5Hz), 3.85(3H, s), 8.13-8.18(1H, m);MP: 140-141 90 Ex6

NMR1: 7.14(1H, d, J=8.8Hz), 4.00 (3H, s), 3.95(3H, s), 2.65(1H, t,J=7.1Hz); MP: 189-191 91 Ex15

NMR2: 1.45-1.52(2H, m), 3.85(3H, s), 6.83-6.88(4H, m); MP: 135-137 0.5H₂O 92 Ex4 4-NEt₂-Ph NMR2: 1.30(6H, t, J=7.0Hz), 3.23 (4H, q, J=7.0Hz),3.82(3H, s); MP: 84-87 93 Ex12 4-(CONMe₂)-Ph NMR2: 2.95(6H, s), 3.82(3H,s), H₂O 7.32(2H, d, J=8.3Hz); MP: 81-83 94 Ex10

NMR2: 2.71(3H, s), 3.82(3H, s), 4.04(2H, t, J=5.3Hz); MP: 183(dec) 2 OxH₂O 95 Ex10

NMR2: 1.33-1.42(2H, m), 3.82(3H, s), 4.52(1H, d, J=3.9Hz); MP: 143-14496 Ex4

NMR2: 6.80(1H, d, J=8.8Hz), 3.85 (3H, s), 3.82(3H, s), 2.78(6H, s); MP:114-115 Ox H₂O 97 Ex21

NMR2: 6.97(1H, d, J=8.6Hz), 4.71 (2H, s), 1.31(3H, t, J=7.3Hz); MP:140-142 98 Ex6

NMR1: 6.97(1H, d, J=8.3Hz), 3.96 (3H, s), 3.94(3H, s), 2.63(2H, t,J=7.4Hz); MP: 153-154 99 Ex21

NMR2: 7.35(1H, dd, J=9.0, 3.4Hz), 4.19(2H, t, J=5.4Hz), 2.78-2.76(4H,m); MP: 163-165 Ox 0.5 H₂O 100 Ex10

NMR2: 3.82(3H, s), 5.09(2H, s), 6.94(4H, s); MP: 137-139 101 Ex10

NMR2: 1.12-1.23(2H, m), 3.82(3H, s), 6.90-6.97(4H, m) MP: 202-205 Ox 0.5H₂O 102 Ex10

NMR2: 2.15(1H, br), 3.82(3H, s), 4.23(2H, t, J=5.3Hz),; F: 533 2 Ox 103Ex10

NMR2: 3.30(3H, s), 3.82(3H, s), 4.00-4.02(2H, m),; MP: 104-108 104 Ex10

NMR2: 3.82(3H, s), 5.12(2H, s), 6.93(4H, s); MP: 140-142 105 Ex21

NMR2: 7.37(1H, dd, J=8.8, 2.4Hz), 4.28(2H, t, J=5.4Hz), 3.85(3H, s),3.82(3H, s); MP: 167-173 Ox 0.5 H₂O 106 Ex6

NMR2: 8.76(1H, d, J=8.8Hz), 3.86 (3H, s), 3.83(3H, s), 2.91(3H, s); MP:135-140 HCl H₂O 107 Ex10

NMR2: 5.06(2H, s), 6.94(4H, s), 8.28(1H, br s); MP: 147-148 108 Ex10

NMR2: 3.82(3H, s), 4.13-4.16(2H, m), 6.88-6.95(4H, m); MP: 109-111 1.5Ox 109 Ex10

NMR2: 3.28(6H, s), 3.82(3H, s), 4.16(2H, t, J=5.4Hz); F: 579 2 Ox 110Ex10

NMR2: 3.82(3H, s), 4.00-4.05(2H, m), 6.86(2H, d, J=8.8Hz); MP: 106-109 2Ox 2 H₂O 111 Ex6

NMR2: 2.79(3H, br s), 3.85(3H, s), 12.06(1H, s); MP: 138-139 H₂O

[0169] TABLE 8

Ex Syn R¹ R² Dat Sal 112 Ex4 MeO cPr—CH₂O NMR1: 7.76(1H, dd, J=8.3,1.0Hz), 2.53 (3H, s), 0.32-0.38(2H, m); MP: 142-144 113 Ex4 MeO Cl NMR1:8.08(1H, d, J=2.5Hz), 7.03(1H, d, J=8.8Hz), 2.53(3H, s); MP: 168-170 114Ex4 MeO CHF₂O NMR1: 7.07(1H, d, J=8.8Hz), 6.62(1H, t, J=74.8Hz),2.54(3H, s); MP: 160-162 115 Ex4 MeO F F: 529 MP: 168-170

[0170] TABLE 9

Ex R⁵ 116 —Et 117 —CHO 118 —(2-Me-Ph) 119 —(3-CF₃-Ph) 120 —(2-F-Ph) 121—(4-Cl-Ph) 122 —(2-OEt-Ph) 123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

[0171] TABLE 10

No R⁵ 1

2

3

4

5

6

7

8

9

10

11

12

[0172] TABLE 11

No R′ 13 4-Pip 14 4-O(CH₂)₃-Pipr 15 4-(CH₂)₃CO₂H 16 4-Pyrr 174-SO(CH₂)₂-Mor 18 4-CH₂NMe₂ 19 4-O(CH₂)₃-Pip 20 4-SO(CH₂)₂-Pipr 214-NMeCH₂CO₂H 22 4-O(CH₂)₃-Pyrr 23 4-SO₂(CH₂)₂-Mor 244-O(CH₂)₃(4-Me-Pipr) 25 4-SO(CH₂)₂-Pip 26 4-SO₂(CH₂)₂-Pipr 274-SO(CH₂)₂NMe₂ 28 4-SO(CH₂)₂-Pyrr 29 4-NH(CH₂)₂-Mor 304-SO(CH₂)₂(4-Me-Pipr) 31 4-SO₂(CH₂)₂-Pip 32 4-NH(CH₂)₂-Pipr 334-SO₂(CH₂)₂NMe₂ 34 4-SO₂(CH₂)₂-Pyrr 35 4-NMe(CH₂)₂-Mor 364-SO₂(CH₂)₂(4-Me-Pipr) 37 4-NH(CH₂)₂-Pip 38 4-NMe(CH₂)₂-Pipr 394-NH(CH₂)₂NMe₂ 40 4-NH(CH₂)₂-Pyrr 41 4-CO-Mor 42 4-NH(CH₂)₂(4-Me-Pipr)43 4-NMe(CH₂)₂-Pip 44 4-CO-Pipr 45 4-NMe(CH₂)₂NMe₂ 46 4-NMe(CH₂)₂-Pyrr47 3-CH═CHCO₂H 48 4-NMe(CH₂)₂(4-Me-Pipr) 49 4-NHCH₂CO₂H 50 2-F-4-OMe 514-CO(4-Me-Pipr) 52 4-(4-Me-Pipr) 53 2-Me-4-OMe 54 4-CONH(CH₂)₂NMe₂ 553-CO₂H 56 3-Ac-4-OMe 57 3-NMe₂ 58 3-Me-4-OMe 59 3,4-diCl 603-NHCO(CH₂)₂NEt₂ 61 3-Ac-4-OH 62 2,4-diF 63 3-NHCO-Pip4 64 2,4-diCl 652,3-diOMe 66 3,4-(OCH₂O) 67 2,3-diF 68 2,3-diCl 69 3,4-diF 70 3,5-diF 713,5-diCl 72 2,4-diOMe 73 3,4-diOMe 74 3,5-diOMe 75 3,4,5-triOMe

[0173] TABLE 12

No: 76

No: 77

No: 78

No: 79

[0174] TABLE 13

No R′ R² = cPr—CH₂—O— 80 4-OCF₃ 81 4-OCHF₂ 82 4-Ac 83 4-CH₂CO₂H 84 4-Mor85 4-(CH₂)₃CO₂H 86 4-OCH₂CO₂H 87 4-Pipr 88 4-O(CH₂)₃CO₂2H 89 4-Pip 904-NHCH₂CO₂H 91 4-CH₂NMe₂ 92 4-Pyrr 93 4-(4-Me-Pipr) 94 4-NMeCH₂CO₂H 954-CO₂H 96 3-Cl 97 4-CO(4-Me-Pipr) 98 3-OMe 99 3-F 100 4-CONH(CH₂)₂NMe₂R² = Cl 101 4-OMe 102 4-Cl 103 4-F 104 3-OCF₃ 105 3-Ac 106 3-O(CH₂)₂NMe₂

1. A pyridine derivative represented by the following general formula(I) or a pharmaceutically acceptable salt thereof:

(wherein each symbol has the following meaning: R¹ and R²: the same ordifferent from each other, H, a halogen, a lower alkyl, O-a lower alkyl,O—(a lower alkyl substituted with halogen(s)), NH₂, NH-a lower alkyl,N(a lower alkyl)₂, NHCO-a lower alkyl, O-a lower alkylene-NH-a loweralkyl, O-a lower alkylene-N(a lower alkyl)₂, O-a lower alkylene-CO₂R⁰,O-a lower alkylene-a hydrocarbon ring or O-a lower alkylene-aheterocycle, or R¹ and R² are combined to form —O-a lower alkylene-O—,R⁰: H, a lower alkyl or CH₂-(an optionally substituted phenyl), R³ andR⁴: the same or different from each other, H, an optionally substitutedlower alkyl, a halogen, CO₂R⁰, CONH₂, CON(R⁰)-(an optionally substitutedlower alkyl), an optionally substituted hydrocarbon ring, an optionallysubstituted heterocycle, CO-(an optionally substituted lower alkyl),CO-(an optionally substituted hydrocarbon ring), CO-(an optionallysubstituted heterocycle) or CN, or R³ and R⁴ are combined to form alower alkylene or oxo, R⁵: H, a lower alkyl, CO₂R⁰, CONH₂, CON (R⁰)-alower alkyl, an optionally substituted hydrocarbon ring, an optionallysubstituted heterocycle, a lower alkylene-an optionally substitutedhydrocarbon ring, a lower alkylene-an optionally substitutedheterocycle, a lower alkenylene-an optionally substituted hydrocarbonring, a lower alkenylene-an optionally substituted heterocycle, an loweralkylene-R⁵¹, a lower alkylene-CO₂R⁰, CO-a lower alkyl, CO-(anoptionally substituted hydrocarbon ring), CO-(an optionally substitutedheterocycle), CO-a lower alkylene-(an optionally substituted hydrocarbonring), CO-a lower alkylene-(an optionally substituted heterocycle),CO—O-a lower alkylene-(an optionally substituted hydrocarbon ring),CO—O-a lower alkylene-(an optionally substituted heterocycle), CON(R⁰)(R⁵⁶), C(R⁵³) (R⁵⁴)-R⁵⁵ or a lower alkylene-C(R⁵³)(R⁵⁴)-R⁵⁵, R⁵¹: CO-alower alkyl, CO-(an optionally substituted hydrocarbon ring), CO-(anoptionally substituted heterocycle), CO-a lower alkylene-(an optionallysubstituted hydrocarbon ring), CO-a lower alkylene-(an optionallysubstituted heterocycle), CN, OH, O-a lower alkyl, O—(an optionallysubstituted hydrocarbon ring), O—(an optionally substitutedheterocycle), O-a lower alkylene-(an optionally substituted hydrocarbonring), O-a lower alkylene-(an optionally substituted heterocycle), S-alower alkyl, S—(an optionally substituted hydrocarbon ring), S—(anoptionally substituted heterocycle), S-a lower alkylene-(an optionallysubstituted hydrocarbon ring), S-a lower alkylene-(an optionallysubstituted heterocycle), NH(R⁰), N(R⁰) 2, N(R⁰)-(an optionallysubstituted hydrocarbon ring), N(R⁰)-(an optionally substitutedheterocycle), N(R⁰)-a lower alkylene-(an optionally substitutedhydrocarbon ring), N(R⁰)-a lower alkylene-(an optionally substitutedheterocycle), N(R⁰)CO-a lower alkyl, N(R⁰)CO-(an optionally substitutedhydrocarbon ring), N(R⁰)CO-(an optionally substituted heterocycle),N(R⁰) CO-a lower alkylene-(an optionally substituted hydrocarbon ring),N(R⁰)CO-a lower alkylene-(an optionally substituted heterocycle),N(R⁰)CO—O-a lower alkyl, N(R⁰)CO—O-a lower alkylene-(an optionallysubstituted hydrocarbon ring) or N(R⁰)CO—O-a lower alkylene-(anoptionally substituted heterocycle), R⁵³, R⁵⁴ and R⁵⁵: the same ordifferent from one another, H, a lower alkyl, CO₂R⁰, CON(R⁰) (R⁵⁶), R⁵¹,or R⁵⁶, R⁵⁶: an optionally substituted hydrocarbon ring, an optionallysubstituted heterocycle, a lower alkylene-an optionally substitutedhydrocarbon ring, a lower alkylene-an optionally substitutedheterocycle, a lower alkylene-R⁵¹ or a lower alkylene-CO₂R⁰, n: 0 or 1,provided that (1) when R⁵ is a group bonded with CO, or H, n represents0, and (2) when both of R³ and R⁴ are each H, R⁵ represents a groupother than methyl, acetyl or benzyl).
 2. The pyridine derivative or apharmaceutically acceptable salt thereof according to claim 1, whereinR¹ is O-a C₁₋₆ alkyl, R² is a halogen, O-a C₁₋₆ alkyl or O-a C₁₋₆alkylene-a hydrocarbon ring, and R³ and R⁴ are each H, a C₁₋₆ alkyl oroxo.
 3. The pyridine derivative or a pharmaceutically acceptable saltthereof according to claim 1, wherein R⁵ is an optionally substitutedhydrocarbon ring or an optionally substituted heterocycle.
 4. Thepyridine derivative or a pharmaceutically acceptable salt thereofaccording to claim 1, which is selected from the group consisting of1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-methoxyphenyl)piperazine,1-(4-{4-[6-(3-cyclopropylmethoxy-4-methoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl)phenyl)ethanone,1-(6-bromo-2-pyridyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine,4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}acetanilide,3-diethylamin-4′-}dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}propananilide,4-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)morpholine,1-[2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenoxy)ethyl]piperidin-4-ol,4-12-[(6-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl)-3-pyridyl)oxy]ethyl}morpholine,trans-5-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethylpiperazin-1-yl}phenyl)pentanoicacid and1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-[(1-oxido-4-pyridyl)methoxy]phenyl)piperadine.
 5. A pharmaceutical composition whichcomprises the pyridine derivative according to claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 6. The pharmaceutical composition according to claim5, which is a type 4 phosphodiesterase inhibitor.
 7. The pharmaceuticalcomposition according to claim 6, which is a preventing or treatingagent for respiratory diseases.
 8. The pharmaceutical compositionaccording to claim 7, which is a preventing or treating agent forbronchial asthma.
 9. The pharmaceutical composition according to claim7, which is a preventing or treating agent for chronic obstructivepulmonary disease (COPD).
 10. A pyridinecarboxylic acid derivativerepresented by the general formula (IIa):

(wherein R^(1a); a halogen, a lower alkyl, O-a lower alkyl, O—(a loweralkyl substituted with halogen(s)), NH₂, NH-a lower alkyl, N(a loweralkyl)₂, NHCO-a lower alkyl, O-a lower alkylene-NH-a lower alkyl, O-alower alkylene-N(a lower alkyl)₂, O-a lower alkylene-CO₂R⁰, O-a loweralkylene-a hydrocarbon ring or O-a lower alkylene-a heterocycle, R^(2a):H or a group described in R^(1a), or R^(1a) and R^(2a) are combined toform —O-a lower alkylene-O—, provided that (1) when R^(2a) is H, R^(1a)represents a group other than methyl, ethyl, OMe, NH₂, NHMe or Cl, and(2) when R^(2a) is methyl, R^(1a) represents a group other than methyl,respectively).